WO 2006/010264 PCT/CA2005/001177
INHIBITORS OF VEGF RECEPTOR AND HGF RECEPTOR SIGNALING
BACKGROUND OF THE INVENTION Field of the Invention
[0001] This invention relates to the inhibition of VEGF receptor signaling and HGF receptor signaling. More particularly, the invention relates to compounds and methods for the inhibition of VEGF receptor signaling and HGF receptor signaling.
Summary of the Related Art
[0002] Angiogenesis is an important component of certain normal physiological processes such as embryogenesis and wound healing, but aberrant angiogenesis contributes to some pathological disorders and in particular to tumor growth.1'2 VEGF-A (vascular endothelial growth factor A) is a key factor promoting neovascularization (angiogenesis) of tumors.3-7 VEGF induces endothelial cell proliferation and migration by signaling through two high affinity receptors, the fins-like tyrosine kinase receptor, Flt-1, and the kinace insert domain-containing receptor, KDR.8,9,10. These signaling responses are critically dependent upon receptor dirnerization and activation of intrinsic receptor tyrosine kinase (RTK) activity. The binding of VEGF as a disulfide-linked homodimer stimulates receptor dimerization and activation of the RTK domain 11.The kinase activity autophosphorylales cytoplasmic receptor tyrosine residues, which then serve as binding sites for molecules involved in the propagation of a signaling cascade. Although multiple pathways are likely to be elucidated for both receptors, KDR signaling is most extensively studied, with a mitogenic response suggested to involve ERK-1 and ERK-2 mitogen-activated protein kinases 12. [0003] Disruption of VEGF receptor signaling is a highly attractive therapeutic target
in cancer, a CLIENT-HOST DIVIDED ARCHITECTURE FOR INPUT-OUTPUT COORDINATION ure endothelium remains relatively quiescent (with the exception ot the temale reproductive system and wound healing). A number of experimental approaches to inhibiting VEGF signaling have been examined, including use of neutralizing antibodies 13,l4,15, receptor antagonists 16, soluble receptors 17, antisense constructs18 and dominant-negative strategies
19
[0004] Despite the attractiveness of anti-angiogenic therapy by VEGF inhibition alone, several issues may limit this approach. VEGF expression levels can themselves be elevated by numerous diverse stimuli and perhaps most importantly, the hypoxic state of tumors resulting from VEGFr inhibition, car. leal to the induction of factors that themselves

WO 2006/010264 PCT/CA2005/001177
promote tumor invasion and metastasis thus, potentially undermining the impact of VEGF inhibitors as cancer therapeutics20
[0005] The HGF (hepatocyte growth factor) and the HGF receptor, c-met, are
implicated in the ability of tumor cells to undermine the activity of VEGF inhibition20.
HGF derived from either stromal fibroblasts surrounding tumor cells or expressed from the
tumor itself has been suggested to play a critical role in tumor angiogenesis, invasion and
metastasis 21,22. For example, invasive growth of certain cancer cells is drastically enhanced
by tumor-stromal interactions involving the HGF/c-Met (HGF receptor) pathway 23,24,25
HGF, which was originally identified as a potent mitogen forhepatocytes26,27 is primarily
secreted from stromal cells, and the secreted HGF can promote motility and invasion of
various cancer cells that express c-Met in a paracrine manner 28,29,30. Binding of HGF to c-
Met leads to receptor phosphorylation and activation of Ras/mitogen-activated protein
kinase (MAPK) signaling pathway, thereby enhancing malignant behaviors of cancer cells
30>31. Moreover, stimulation of the HGF/c-met pathway itself can lead to the induction of
VEGF expression, itself contributing directly to angiogenic activity32'
[0006] Thus, anti-tumor anti-angiogenic strategies or approaches that target both
VEGF/VEGFr signaling and HGF/c-met signaling may circumvent the ability of rumor cells
to overcome VEGF inhibition alone and may represent improved cancer therapeutics.
[0007] Here we describe small molecules that are potent inhibitors of both the VEGF
receptor KDR and the HGF receptor c-met.
BRIEF SUMMARY OF THE INVENTION
[0008] The present invention provides new compounds and methods for treating cell
proliferative diseases. The compounds of the invention are dual function inhibitors, capable
of inhibiting both VEGF and HGF. Accordingly, the invention provides new inhibitors of
VEGF receptor signaling and HGF receptor signaling, including the VEGF receptor KDR
and the HGF receptor c-met.
[000S] In a first aspect, the invention provides compounds of formula A that are
useful as inhibitors of VEGF receptor signaling and HGF receptor signaling.
[0010] In a second aspect, the invention provides compounds of formula B that are
useful as inhibitors of VEGF receptor signaling and HGF receptor signaling.
[0011] In a third aspect, the invention provides compositions comprising a compound
of the present invention that is an inhibitor of VEGF receptor signaling and HGF receptor
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signaling, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable
carrier, excipient, or diluent.
[0012] In a fourth aspect, the invention provides a method of simultaneously
inhibiting VEGF receptor signaling and HGF receptor signaling in a cell, comprising
contacting a cell in which inhibition of VEGF receptor signaling and HGF receptor
signaling is desired with a compound of the invention.
[0013] The foregoing merely summarizes certain aspects of the invention and is not
intended to be limiting in nature. These aspects and other aspects and embodiments are
described more fully below.
DETAILED DESCRIPTION OF TIIE PREFERRED EMBODIMENTS [0014] The invention provides compounds and methods for inhibiting the VEGF receptor iCDR and the HGF receptor c-met. The invention also provides compositions and methods for treating cell proliferative diseases and conditions. The patent and scientific literature referred to herein establishes knowledge that is available to those with skill in the art. The issued patents, applications, and references that are cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference. In the case of inconsistencies, the present disclosure will prevail.
[0015] For purposes of the present invention, the following definitions will be used (unless expressly stated otherwise):
[0016] The terms" inhibitor of VEGF receptor signaling" and "inhibitor of HGF receptor signaling" are used to identify a compound having a structure as defined herein, which is capable of interacting with a HGF receptor and a VEGF receptor and inhibiting the activity of HGF and VEGF. In some preferred embodiments, such reduction of activity is at least about 50%, more preferably at least about 75%, and still more preferably at least about 90%.
[0017] For simplicity, chemical moieties aie defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an "alkyl" moiety generally refers to a monovalent radical (e.g. CH3-CH2-), in certain circumstances a bivalent linking moiety can be "alkyl," in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term "alkylene."
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(Similarly, in circumstances in which a divalent moiety is required and is stated as being "aryl," those skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2,4, or 6 for S, depending on the oxidation state of the S). On occasion a moiety may be defined, for example, as (A)3-B-, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B- and when a is 1 the moiety is A-B-. Also, a number of moieties disclosed herein exist in multiple tautomeric forms, all of which are intended to be encompassed by any given tautomeric structure.
10018] The term "hydrocarbyl" refers to a straight, branched, or cyclic alkyl, alkenyl, or alkynyl, each as defined herein. A "Co" hydrocarbyl is used to refer to a covalent bond. Thus, "Co-Cj-hydrocarbyl" includes a covalent bond, methyl, ethyl, ethenyi, ethynyl, propyl, propenyl, propynyl, and cyclopropyl.
[0019] The term "alkyl" as employed herein refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkyl groups include, without limitation, methyl, ethyl, propy], isopropyi, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. A "Co" alkyl (as in "Cc-C3.alkyl") is a covalent bond (like "C" hydrocarbyl).
[0020] The term "alkenyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkenyl groups include, without limitation, ethenyi, propenyl, butenyi, pentenyl, and hexenyl. [0021] The term "alkynyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms, and more preferably 2-6 carbon atoms, which is optionally substituted with one, two or three substituents. Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl. [0022] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Preferred alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Preferred alkenylene groups include, without limitation,
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ethenylene, propenylene, and butenylene. Preferred alkynylene groups include, without limitation, ethynyiene, propynylene, and butynyiene.
[0023] The term "cycloalkyl" as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 lo 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
[0024] The term "heteroalkyl" refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from the group consisting of O, S, NH, N-alkyl, SO, SO2, SO2NH, orNHSO2. [0025] An "aryl" group is a C6-Cu aromatic moiety comprising one to three aromatic rings, which is optionally substituted. Preferably, the aryl group is a C
[0026] A "heterocyclyl" or "heterocyclic" group is a ring structure having from about 3 to about 12 atoms, wherein one or more atoms are selected from the group consisting of N, O, S, SO, and SO2. The heterocyclic group is optionally substituted on carbon at one or more positions. The heterocyclic group is also independently optionally substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl. Preferred heterocyclic groups include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino. In certain preferred embodiments, the heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl group. Examples of such fused heterocyles include, without limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically excluded from the scope of this term are compounds where an annular O or S atom is adjacent to another O or S atom.
[0027] As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6,10, or 14 rc-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring
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selected from the group consisting of N, 0, and S. The term "heteroaryl" is also meant to encompass rnonocyclic and bicyclic groups. For example, a heteroaryl group may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl, benzofuranyl and indolinyi. A "heteroaralkyl" or "heteroarylalkyl" group comprises a heteroaryl group covalently linked to an alkyl group, either of which is independently optionally substituted or unsubstituted. Preferred heteroalkyl groups comprise a Ci-Ce alkyl group and a heteroaryl group having 5, 6,9, or 10 ring atoms. Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms. Examples of preferred heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, and thiazolylethyl. Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms. [0028] For simplicity, reference to a "Cn-Cm" heterocyclyl or heteroaryl means a heterocyclyl or heteroaryl having from "n" to "m" annular atoms, where "n" and "m" are integers. Thus, for example, a Cs-Cg-heterocyclyl is a 5- or 6- membered ring having at least one heteroatom, and includes pyrrolidinyl (Cs) and piperidinyl (Ce); C6-hetoaryl includes, for example, pyridyl and pyrimidyl.
[0029] An "arylene," "heteroarylene," or "heterocyclylene" group is an aryl,
heteroaryl, or heterocyclyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.
[0030) Preferred heterocyclyls and heteroaryis include, but are not limited to,
acrid inyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, pyridotriazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-bjtetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyi, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochrotnanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyI, oxazotidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,
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cycloalky!, heterocyclyl, or heteroaryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above; or R3C and R31 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents from (a), above.
[0032] Especially preferred substituents on allcyl groups include halogen and hydroxy,
[0033] Especially preferred substituents or ring groups, such as aryl, heteroaryl,
cycloalkyl and heterocyclyl, include halogen, alkoxy and alky].
[0034] A "halohydrocarbyl" is a hydrocarbyl moiety in which from one to all
hydrogens have been replaced with one or more halo.
[0035] The term "halogen" or "halo" as employed herein refers to chlorine, bromine,
fluorine, or iodine. As herein employed, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent. The term "acvlamino" refers to an amide group attached at the nitrogen atom (i.e., R-CO-NH-). The term "carbamcyl" refers to an amide group attached at the carbonyl carbon atom (i.e., NH2-CO-). The nitrogen atom of an acylamino or carbamoyl substituent is additionally substituted. The term "sulfonamido" refers to a sulfonamide substituent attached by either the sulfur or the nitrogen atom. The term "amino" is meant to include NH2, alkylamino, arylamino, and cyclic amino groups. The term "ureido" as employed herein refers to a substituted or unsubstituted urea moiety. [0036] The term "radical" as used herein means a chemical moiety comprising one or more unpaired electrons.
[0037] A moiety that is substituted is one in which one or more hydrogens have been
independently replaced with another chemical substituent. As a non-limiting example, substituted phenyls include 2-flurophenyl, 3,4-dichlorophenyl, 3-chIoro-4-f!uoro-phenyl, 2-fluoro-3-propylphenyl. As another non-limiting example, substituted n-octyls include 2,4-dimethyl-5-ethyi-octyl and 3-cyclopentyl-octyl. Included within this definition are methvlenes (-CH2-) substituted with oxygen to form carbonyl -CO-). [0038] An "unsubstituted" moiety as defined above (e.g., unsubstituted cycloalkyl, unsubstituted heteroaryl, etc.) means that moiety as defined above that does not have any of the optional substituents for which the definition of the moiety (above) otherwise provides. Thus, for example, while an "aryl" includes phenyl and phenyl substituted with a halo, "unsubstituted aryl" does not include phenyl substituted with a halo.

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[0039] Throughout the specification, preferred embodiments of one or more chemical substituents are identified. Also preferred are combinations of preferred embodiments. For example, paragraph [0048] describes preferred embodiments of X and X1 in the compounds of formula (A) and paragraph [0053] describes preferred embodiments of R1 in the compounds of formula (A). Thus, also contemplated as within the scope of the invention are compounds of formula (A) in which X and X1 are as described in paragraph [0048] and R1 is as described in paragraph [0053]. Furthermore, compounds excluded from any one particular genus of compounds (e.g., through a proviso clause) are intended to be excluded from the scope of the invention entirely, including from other disclosed genera, unless expressly stated to the contrary.
Compounds
[0040J In the first aspect, the invention comprises compounds of formula (A), that are inhibitors of VEGF receptor signaling and HGF receptor signaling:

WO 2006/010264 PCT/CA2005/O0117'
W is selected from the group consisting of O, S, NH and NMe;
Z is selected from the group consisting of O, or S and NH;
X and X1 are independently selected from the group consisting of H, CpC6 alkyl, halo, cyano, or nitro, wherein CpC^ alkyl is optionally substituted, or
X and X1 taken together with the atom to which they are attached, form a C3-C7 cycloalkyl;
R\ R2, R3 and R4 independently represent hydrogen, halo, trihalomethyl, -CN, -NO2, -NH2, -OR'7, -NR17R18, -C(O)OR17, -C(O)R17, C-C4 alkoxy, CrC4 alkylthio, C,~C6 alkyl, C2-C6 alkenyl or C2-Co alkynyl, wherein C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl are optionally substituted;
R17 is selected from the group consisting of H and R18;
R!S is selected from the group consisting of a (Ci-C6)alkyl, an aryl, a aryl(Ci-Q)alkyl, a
heterocyclyl and a heterocyclyl(Ci-C6)alkyi, each of which is optionally substituted, or
R17 and R1S, taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, the optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from the group consisting of N, 0, S and P;
R16 is selected from the group consisting of-H, -CN, -(CH2)o-5(aryl), -(CH2)o-s(heteroaryl), C|-Cri alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2(CH2)(M-T2, an optionally substituted C14 alkylcarbonyl, and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMe, -OEt, -NH2, -NHMe, -NMe2, -NHEt and -NEt2, and wherein the aryl, heteroaryl, C1-C6 alkyl, C2-Ce alkenyl, and C2-C6 allcynyl are optionally substituted;
Q is selected from the group consisting of CH2,0, S, N(H), N(CrC6 alkyl), N-Y-(aryl), -N-
OMe, -NCH2OMe and -N-Bn;
D is selected from the group consisting of C-E and N;
L is N, or CR, wherein R is selected from the group consisting of -H, halo, -CN, C1-C6
alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein C,-C
E is selected from the group consisting of E1, E2 and E3, wherein
E! is selected from the group consisting of-H, halogen, nitro, azido, C1-C6 alkyl, C3-C10 cycloalkyl, -C(O)NR42R43, -Y-NR42R43, -NR42C(O)R43, -SO2R42, -SO2NR42R43, -NR37SO2R42, -NR37SO2NR42R43, -C(=N-OR42)R43, -C(=NR42)R43, -NR37C(=NR42)R43,
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heterocyclyl), -(CH2)nO(CH2)iOR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6;
each R42 and R43 is independently selected from the group consisting of H, C\~C6 alkyl, C\-C6 heteroalkyl, -Y-(C3-C!0 cycloalkyl), -Y-(C6-C]0 aryl), -Y-(C6-Ci0 heteroaryl), -Y-(5-10 membered heterocyclic), -Y-O-Y'-OR37, -Y'-CO2-R37, and -Y-OR37, wherein the alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic moieties of the foregoing R42 and R43 groups are optionally substituted by 1 or more substituents independently selected from R44, wherein
Y is a bond or is -(C(R37)(H))n,
n is an integer ranging from 1 to 6, and
Y1 is -(C(R37)(H))n, or
R42 and R43 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted by 1 to 5 independently selected R44 substituents, with the proviso that R42 and R43 are not both bonded to the nitrogen directly through an oxygen;
each R44 is independently selected from the group consisting of halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -NR36R39, -OR37, -SO2NR36R39, -SO2R36, -NR36SO2R39, -NR36SO2NR37R4\ CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, -CrC6 alkylamino, -(CH2)jO(CH2)1NR36R39, -(CH2)nO(CH2)iOR37> -(CH2)nOR37, -SCO^Ci-Cg alkyl), -(CH2)n(C6-C,o aryl), -(CH2)n(5-10 membered heterocyclic), -C(O)(CH2)n(C6-C10 aryl), -(CH2)nO(CH2)j(C6-C10 aryl), -(CH2)nO(CH2)i(5 to 10 membered heterocyclic), -C(O)(CH2)n(5 to 10 membered heterocyclic), -(CH^jNR^CH^NR^R39, -(CH2)jNR39CH2C(O)NR36R39, -(CH2)jNR39(CH2)iNR37C(O)R40, -(CH2)jNR39(CH2)nO(CH2)iOR37, -(CH2)jNR39(CH2)iS(O)j(CI-C6 alkyl), -(CH2)jNR39(CH2)nR36, -SO2(CH2)n(C6-C10 aryl), and -SO2(CH2)n(5 to 10 membered heterocyclic) wherein,] is an integer from 0 to 2, n is an integer from 0 to 6 and i is an integer ranging from 2 to 6, the -(CH2)i-and -(CH2)ni- moieties of the foregoing R44 groups optionally include a carbon-carbon double or triple bond wherein n is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R44 groups are optionally substituted by 1 or more substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -OH, -C(O)R40, -C(O)OR40, -OC(O)R'
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C3-C10 cycloalkyl, -(CH2)n(C6-Cio aryl), -(CHiM.S to 10 membered heterocyclic), -(CH2)n0(CH2)i0R37 and -(CH2)nOR37, wherein n is an integer from 0 to 6 and i is an integer from 2 to 6; and
each R40 is independently selected from H, d-Cio allcyl, -(CH2)n(C6-C10 aryl), CrCto
cycloalkyl, and -(CH2)n(5-10 membered heterocyclic), wherein n is an integer ranging from 0 to 6;
each R36 and R39 is independently selected from the group consisting of H, -OH, Ci-Cg alkyl, C3-C10 cycloalkyl, -(CH2)n(C6-Cio aryl), -(CH2)n(5-10 membered heterocyclic), -(CH2)nO(CH2),OR37, -(CH2)nCN(CH2)nOR37, -(CH2)nCN(CH2)nR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R36 and R39 groups are optionally substituted by one or more substiuients independently selected from -OH, halo, cyano, nitro, trifluoromethyl, azido, -C(O)R40, -C(O)OR40, -CO(O)R40, -OC(O)OR40, -NR37C(O)R41, -C(O)NR37R41, -NR37R41, -CrC6 alkyl, -(CH2),,(C6-Cio aryl), -(CH2)n(5 to 10 membered heterocyclic), -(CH2)nO(CH2)iOR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, with the proviso that when R36 and R39 are both attached to the same nitrogen, then R36 and R39 are not both bonded to the nitrogen directly through an oxygen;
each R37 and R4! is independently selected from the group consisting of H, OR36, CpCe
alkyl and C3-C10 cycloalkyl;
each R6a and R6b is independently selected from the group consisting of hydrogen, -(CZ5zV(C3-C6)cycloalkyl, -(CZ5Z6)u-(C5-C6)cycloalkenyl, -(CZ5Z6)u-ary!, -(CZ5zVheteroaryl, -(CZsZ6)u-heterocycle, (C2-Gs)alkenyl, and (CrCV)alkyl, each of which is optionally substituted with 1 to 3 independently selected Y3 groups, where u is 0,1,2, or 3, and wherein when u is 2 or 3, the CZ5Z6 units may be the same or different, or
R6a and R6b taken together with adjacent atoms can form a heterocycle;
each Z3, Z4, Z5 and Z6 is independently selected from the group consisting of H, F and (Cr C6)alkyl, or
each Z3 and Z4, or Z5 and Z6 are selected together to form a carbocycle, or
two Z3 groups on adjacent carbon atoms are selected together to optionally form a carbocycle;
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each Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, araidino, methylguanidino, azido, -C(O)Z7, -OC(O)NH;>, -OC(O) NHZ7, -OC(O)NZ7Z8, -NHC(O)Z7, -NHC(0)NH2, -NHC(0)NHZ7, -NHC(O)NZ7Z8, -C(O)OH, -C(O)OZ7, -C(O)NH2) -C(O)NHZ7,-C(O)NZ7Z8, -P(O)3H2, -P(O)3(Z7)2, -S(O)3H, -S(O)Z7, -S(O)2Z7, -S(O)3Z7, -Z7, -OZ7, -OH, -NH2, -NHZ7, -NZ7Z8, -C(=NH)NH2,-C(=NOH)NH2) -N-morpholino, (CrC6)alkyl, (C2-C6)alkenyl, (C2-Cs)alkynyl, (C,-C6)haloalkyl, (C2-C6)haloalkenyl, (C2-C6)haloaikynyl, (Ci-C6)haloalkoxy, -(CZ9Z10)rNH2) -(CZ9Zl0)tNHZ3, -(CZ9Z10)rNZ7Z*, -X6(CZ9Z10)r-(C3-C8)cycloalkyl, -X6(CZ9Z10)r-(C5-C8)cycloalkenyl, -X6(CZ9Z10)r-aryl and -X6(CZ9Z'V heterocycle, wherein ris 1,2, 3 or 4; X6 is selected from the group consisting of O, S, NH, -C(O)-, -C(O)NH-, -C(O)O-5 -S(O>, -
S(O)2- and -S(O)3-;
Z7 and Z8 are independently selected from the group consisting of an alkyl of 1 to 12 carbon atoms, an alkenyl of 2 to 12 carbon atoms, an alkynyi of 2 to 12 carbon atoms, a cycloalkyl of 3 to 8 carbon atoms, a cycloalkenyl of 5 to 8 carbon atoms, an aryl of 6 to 14 carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7 to 15 carbon atoms, and a heteroaralkyl of 5 to 14 ring atoms, or Z7 and Z8 together may optionally form a heterocycle;
Z9 and Z10 are independently selected from the group consisting of H, F, a (C]-Ci2)alkyl, a (C
two Z9 groups on adjacent carbon atoms are taken together to form a carbocycle; or any two Y2 or Y3 groups attached to adjacent carbon atoms may be taken together to be -
OfCCZ^CZ10)]^ or -Otqz'XZ'0)]^,, or any two Y2 or Y3 groups attached to the same or adjacent carbon atoms may be selected
together to form a carbocycle or heterocycle; and wherein
any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not attached to a halogen, SO or SO? group or to a N, O or S atom optionally bears on said group a substituent selected from hydroxy, halogen, (Ci-C4)alkyl, (Cj-C^alkoxy and an -N[(C,-C4)alkyl][(CrC4)alkyl]; E2 is -OCH or -OC-tCR^R'VR46;
R45 is independently selected from the group consisting of H, a (Ci-Cb)alkyl and a (C3-Cg)cycloalkyl;
14

WO 2006/010264 PCT/CA2OO5/OO1177
R46 is selected from the group consisting of heterocyclyi, -N(R47)-C(O)-N(R4;)(Rltt), -N(R47)~C(S)-N(R47)(R48), -N(R47)-C(O)-OR4S, -N(R47)-C(O)-(CH2)n-R48, -N(R47)-SO2R47S -(CH2)nNR47R48, -(CH2)nOR4t, -(CH2)nSR49, -(CH2)n3(O)R49, -(CH2)nS(O)2R49, -OC(O)R49, -OC(O)OR49, -C(O)NR47R48, heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-Cfijalkoxy, -NO2, (CrC6)alkyl, -CN, -SO2R50 and -(CH2)nNR50R51, and aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-OOalkoxy, -NO2, (Cj-C6)alkyl, -CN, -SOiR50 and -(CH2)nNR5f)R51;
R47 and R48 are independently selected from the group consisting of H, (Ci-C6)alkyl, (C3-C8)cycloaUcyI, heterocyclyi, -(CH2)nNR5OR51) -(CH^OR50, -(CH2)nC(O)R49, -C(O)2R49, -(CH2)nSR49, -(CH2)nS(O)R"9) -(CH2)nS(O)2R49, -(CH,)^49, -(CH2)nCN, aryl optionally substituted wiih one or more substituents selected from the group consisting of haio, -CF3, (Ci-C6)alkoxy, -NO2, (Ci-C6)alkyl, -CN, -(CH2)nOR495 -(CH2)nheterocyclyl, -(CH2),,heteroaryl, -SO2R50 and -(CH2)nNR50R51, and heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3; (Q-Qalkoxy, -NO2, (C|-C6)alkyl, -CN, -(CH2)nOR49, -(CH2)nheterocyclyl, -(CH2)nheteroaryl, -SO2RS0 and -(CH2)nNRi0R5i, or
R47 and R48, together with the atom to which they are attached, form a 3-8 membered ring;
R*9 is selected from the group consisting of (Ci-QOalkyl, (C3-Cs)cycloalkyl,
heterocyclyl(Ci-C6)alkylene, aryl(Ci-C6)alkylene wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, (C-QOalkyl, -CN, -SO2R50 and -(CH2)nNR50R51, heteroaryl(Ci-C6)alkylene wherein the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (d-C6)alkoxy, -NO2, (CrC6)alkyl, -CN, -SO2R50 and -(CH2)nNRs0R51, aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (C\-C6)alkoxy, -NQ2, (Ci-C6)allcyl, -CN, -SO2R50 and -(CH2)nNR50R51, and heteroaryl optionahy substituted with one or more substituents selected from the group consisting of halo, -CF3, (C,-C6)alkoxy, -NO2, (C,-C6)alkyl, -CN, -SO2R50 and -(CH2)r,NR50R5!;
R50 and R51 are independently selected from the group consisting cf H, (C)-C6)alkyl, (C3-C«)cycloalkyl and -C(O)R45, or
15

WO 2006/010264 POT/CA2005/001177
R50 and R51, together with the atom to which they are attached, form a 3-8 membered ring;
and
E3 is the group defined by -(Zn)-(Z'V(Z13)mb wherein Zu is heterocyclyl or heterocyclylene;
Z12 is selected from the group consisting of OC(O), OC(S) and C(O); Z!3 is selected from the group consisting of heterocyclyl, aralkyl, N(H)R52, (d-CsJalkyl, -
OR52, halo, S(O)2R56, (CrC3)hydroxyalkyl and (C|-C3)haloalkyl; m isOor 1; ml isOor 1; R52 is selected from the group consisting of H, -(CH2)qS(O)2R54, R55NR53R53, (Ci-C3)alkyl,
-(CH2)qOR53, -C(O)R54 and -C(O)OR53; q is 0,1, 2, 3 or 4; R53 is (Ci-C3)alkyl; R54 is (C,-C3)alkyl or N(H)R53; R53 is (CrC6) alkyl; and
R56 is selected from the group consisting of NH2, (Ci-C3)alkyl and OR52.
[0041] In a preferred embodiment of the compounds according to paragraph [0040], T
is aryl or heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with 1 to 3 independently selected R20.
[0042] In a preferred embodiment of the compounds according to paragraph [0040], T
is selected from the group consisting of arylalkyl, cycloalkyl and heterocyclyl, wherein each of said arylalkyl, cycloalkyl and heterocyclyl is optionally substituted with 1 to 3 independently selected R20.
[0043] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0042], R20 is selected from the group consisting of H, halogen, -OR17 and -C(O)OR17.
[0044] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0043], R20 is fluorine or chloride.
[0045] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0044], W is O.
[0046] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0045], Z is S or O,
[0047] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0046], Z is S.
16

WO 2006/010264 PCT/CA20O5/001177
[0048] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0047], X and X1 are independently selected from the group consisting of H and d-
C6alkyl, wherein the CrCgalkyl is optionally substituted.
[0049] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0048], X and X1 are both H.
[0050] In a preferred embodiment of the compounds according to paragraphs [0040]
to f0048], X and X1 taken together with the atom to which they are attached, form a C3-
C7cycloalkyl.
[0051] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0050], Rl, R2, R3 and R4 are independently selected from the group consisting of H,
halogen, trihalomethyl, OR17, -NR17R18 and Ci-C6alkyl.
[0052] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0051], R1, R2 and R4 are independently selected from the group consisting of H, halo and
-OR17.
[0053] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0052], R1 is H or halogen.
[0054] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0053], Rl is halogen.
[0055] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0054], R2, R3 and R4 are each H.
[0056] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0055], R17 is a CrC6alkyl.
[0057] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0056], R16 is H or Ci-C6alkyl.
[0058] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0057], Q is selected from the group consisting of CH2, S, -N-(Ci-C6alkyl), N-Y-(aryl)
and -N-OMe.
[0059] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0058], Q is S.
[0060] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0058], Q is CH2.
[0061] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0058], Q is -N-(Ci-C6alkyl).
17

NVO 2M6/010264 PCT/CA2005/«H)l 177
£0062] In a preferred embodiment of the compounds according to paragraphs [0040}
to [0058], Q is -N-Y-(aryl).
[0063] In a preferred embodiment of the compounds according to paragraphs [0040] to [0058], Q is -N-OMe.
[0064] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0063], D is C-E.
[00661 In a preferred embodiment of the compounds according to paragraphs [0040]
to [0064], D is CH.
[0066] In a preferred embodiment of the compounds according to paragraphs [0040] to [0065], L is C-R.
[0067] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0065], R is H or halogen.
[0068] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0065], L is N.
[0069] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0068], E is selected from the group consisting of E1 and E2.
[0070] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0069], EisE1.
[0071] In a preferred embodiment of the compounds according to paragraphs [0040] to [0070], E is E1, wherein E1 is selected from the group consisting of H, halogen, -C(O)NR42R43, -SO2NR42R43, C(=NR42)NR37R43, -CO2R42, -C(O)(heterocyclyl), -C(O)(heteroaryI), -Y-(C6-Ci0 aryi), -Y-(heteroaryl), -Y-(5 to 10 membered heterocyclic), -SR6a, -S(O)R6a, -SO2R6a, wherein each of said E1 other than H and halogen are optionally substituted with 1 to 5 independently selected R38, or El is (Cl-C6)alkyl, which is optionally substituted with 1 to 3 independently selected Y2 groups. [0072] In a preferred embodiment of the compounds according to paragraphs [0040] to [0071], R38 is selected from the group consisting of halogen, -C(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -NR36R39, -OR37, Ci-C6alkyl, -C(CH2)jO(CH2)iNR36R39, -(CH2)nOR37, -S(O)j(C,-C6alkyl), -(CH2)n-(5 to 10 membered heterocyclic), -(CH2)O(CH2)i(5 to 10 membered heterocyclic), -(CH2)n(5 to 10 membered heteroaryl), -(CH2)jNR39(CH2)iNR36R39, -(CH2),NR39(CH2)nR36, ~(CH2)nNR36R39: wherein j is an integer ranging from 0 to 2, n is an integer ranging from 0 to 6, i is an integer ranging from 1 to 6,, the -(CH2);- and -(CH2)n- moieties of the foregoing R38 groups optionally include a carbon-carbon double or triple bond where n is an integer between 2 and 6, and the alkyl, ary],
18

WO 2006/010264 PCT/OA2005/001177
heteroaryl, and heterocyclic moieties of the foregoing R38 groups are optionally substituted
by one or more substituents independently selected from the group consisting of halo,
cyano, nitro, trifluoromethyl, azido, -OH, -C(O)R40, -C(0)OR4°, -OC(O)R40, -OC(O)OR40, -
NR36C(O)R39, -C(O)Mt36R39, -(CH2)nNR36R39, C,-C6 alkyl, C3-C,o cycloalkyl, -(CH2)n(C6-
Cio aryl), -(CH2)n(5-10 membered heterocyclyl), -(CH2)nO(CH2)iOR37, and -(CH2)nOR37,
wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6.
[0073] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0072], the alkyl, aryl, heteroaryl, and heterocyclic moieties of the foregoing R38 groups
are optionally substituted by one or more subslituents independently selected from the
group consisting of-OH and -C(O)OR40.
[0074] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0073], each R42 and R43 is independently selected from the group consisting of H, -Y-
(C3-C10 cycloalkyl), -Y-(C6-Cto aryl), -Y-(C6-C]0 heteroaryl) and -Y-(5 to 10 membered
heterocyclic), wherein the cycloalkyl, aryl, heteroaryl and heterocyclic moieties of the
foregoing R42 and R43 groups are optionally substituted by 1 or more substituents
independently selected from R44.
[0075] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0073], each R42 and R43 is independently selected from the group consisting of II, Ci-Ce
alkyl, d-Co heteroalkyl, -Y'-CO2-R37 and -Y-OR37.
[0076] In a preferred embodiment of the compounds according to paragraphs
[0040]to [0075], one of R42 and R43 is H.
[0077] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0076], one of R42 and R43 is -(C6-C10 heteroaryl) or -Y-(5 to 10 membered heterocyclic).
[0078] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0077], Y is a bond.
[0079] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0077] Y is -(C(R37)(H))n.
[0080] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0079], R42 and R43 taken together with the nitrogen to which they are attached form a
C5-C9 heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted by 1
to 5 independently selected R44 substituents, with the proviso that R42 and R43 are not both
bonded to the nitrogen directly through an oxygen.
19

WO 2006/(110264 PCT/CA2005/001177
[0081] 111 a preferred embodiment of the compounds according to paragraphs [0040]
to [0080], R44 is independently selected from the group consisting of-C(O)NR36R39, -OR37
and CrC6allcyl.
[0082] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0081], each R'10 is independently selected from the group consisting of H and CJ-CJO
alkyl.
[0083] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0082], each R3° andR39 is independently selected from the group consisting of H, Q-
C6alkyl, -(CH2)n(5 to 10 membered heterocyclic), -(CH2)nOR37 and -C(O)OR40, wherein n is
an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, with the proviso that
when R36 and R39 are both attached to the same nitrogen, then R36 and R39 are not both
bonded to the nitrogen directly through an oxygen.
[0084] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0083], each R37 and R4! is independently selected from the group consisting of H and
Ci-C6alkyl.
[0085] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0084], R6a is selected from the group consisting of-(CZ5Z6)u-aryl, -(CZsZ6)u-heteroaryl
and Ci-Cgalkyl, each of which is optionally substituted with 1 to 3 indepedently selected Y3
groups, wherein u is 0, 1,2 or 3, and wherein when u is 2 or 3, the CZ5Z6 units may be the
same or different.
[0086] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0085], R6a is selected from the group consisting of-(CZ5Z6)u-aryl and -(CZ5Z6)U-
heteroaryl, each of which is optionally substituted with 1 to 3 indepedently selected Y3
groups, wherein u is 0.
[0087] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0086], Y2 is -OH.
[0088] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0086], Y3 is -OH.
[0089] In a preferred embodiment of the compounds according to paragraphs [0040]
to [0069], E2 is -CsC-(CR45R45)n-R451 wherein n is an integer ranging from 1 to 6.
[0090] In a preferred embodiment of the compounds according to paragraph [00S9],
R45 is H.
[0091] In a preferred embodiment of the compounds according to paragraph [0089] to
[0090], R46 is a heterocyclyl.
20

WO 2006/010264 PCT/CA2005/001177
[0092] In a preferred embodiment of the compounds according to paragraph [0040],
the compounds are represented by the formula A-0:

WO 21)06/010264 PCT/CA2005/001177
Rn at each occuiTence is independently H or C1-C6 alkyl, wherein Cj-Cs alkyl is optionally
substituted, each R20 is independently selected from the group consisting of hydrogen, halo,
trihalomethyl, OR17, C1-C0 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein Ci-C6
alkyl, C2-C6 a!kenyl and C2-C6 alkynyl are optionally substituted, and each R17 is an independently selected Ci-Cealkyl, wherein said Ci-C6alkyl is optionally
substituted.
[0093] In a preferred embodiment of the compounds according to paragraph [0092], X and X1 are both hydrogen.
[0094] In a preferred embodiment of the compounds according to paragraphs [0092] to [0093], R1 is hydrogen or halogen.
[0095] In a preferred embodiment of the compounds according to paragraphs [0092]
to [0094], R1 is fluorine.
[0096] In a preferred embodiment of the compounds according to paragraphs [0092]
to [0095], R4 is hydrogen or halogen.
[0097] In a preferred embodiment of the compounds according to paragraphs [0092]
to [0096], R4 is fluorine.
[0098] In a preferred embodiment of the compounds according to paragraphs [0092]
to [0097], R2 is selected from the group consisting of H, haiogen, trihalomethyl and -OR17.
[0099] In a preferred embodiment of the compounds according to paragraphs [0092 j
to [0098], R3, and R2Oare each hydrogen.
[0100] In a preferred embodiment of the compounds according to paragraphs [0092] to [0098], R20 is -OR17.
[0101] In a preferred embodiment of the compounds according to paragraphs [0092] to [0100], Q is S, N(Ci-C6 alkyl), or N-Y-(aryl).
[0102] • In a preferred embodiment of the compounds according to paragraphs [0092] to [0100],QisNH.
[0103] In a preferred embodiment of the compounds according to paragraphs [0092] to [0102],DisCRn.
[0104] In a preferred embodiment of the compounds according to paragraphs [0092] to [0103],LisCHorN.
[0105] In a preferred embodiment of the compounds according to paragraphs [0092] to [0104], R7 is H, halogen, Cj-C6 alkyl, -CONR9R10, -SO2NH2, -SO2NR9R!0, -Y-heterocyclyl, -Y-heteroaryh -S-aryi, -S-C,-C6 alkyl, -SO-Ci-Q alkyl, or -SO2-CrC6 alkyl, wherein Q-Q
22

WO 2006/010264 PCT/CA2005/001177
alky I, is unsubstituted or is substituted with one or two of hydroxy or halogen, and
heterocyclyl, and heteroaryl are unsubstituted or substituted with one or two of alkoxy,
alkyl, or haloalkyl.
[0106] In a preferred embodiment of the compounds according to paragraphs [0092] to
[0105], R7 is -CONR9R10.
[0107] In a preferred embodiment of the compound according to paragraphs [0092] to
[0105],R7isY-heteroaryl.
[0108] In a preferred embodiment of the compounds according to paragraph [0106], R9
and Rt0 are independently H, C,-C6 alkyl, -Y-O-R11, -Y-(heterocycle), -Y'-CQrR11, or -Y-
(aryl), wherein C]-Ce alkyl is unsubstituted or is substituted with one or two of hydroxy or
halogen, and heterocyclyl, and aryl are unsubstituted or are substituted with one or two of
alkoxy, alkyl, or haloalkyl.
[0109] In a preferred embodiment of the compounds according to paragraph [0106], R9
and R10 are taken together with the nitrogen to which they are attached to form a
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl ring, wherein said
ring is unsubstituted or is substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0110] In a preferred embodiment of the compounds according to paragraphs [0092] to
[0105], R7 is H, halogen, CrC6 alkyl, -SO2NR9R10, -C(=O)(heterocyc!yI), -Y-
(heterocyclyl), or -Y-(heteroaryl), wherein d-Cg alkyl is unsubstituted or is substituted with
one or two of hydroxy or halogen, and heterocyclyl, and heteroaryl are unsubstituted or are
substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0111] In a preferred embodiment of the compounds according to paragraphs [0092] to
[0110], Z is sulfur.
[0112] In a preferred embodiment of the compounds according to paragraph [0040], the
compounds are represented by the formula A-l:

WO 2(106/010264 PCT/CA2005/IMI1177
R1 is selected from the group consisting of hydrogen, halo, C]-C6 alkyl, C2-C6 alkenyl or
C2-C6 alkynyl, wherein Ci-C0- alkyl, C2-Q alkenyl and C2-C6 alkynyl are optionally
substituted;
X and X1 are independently selected from the group consisting of H and CrC6 alkyl, wherein Q-C6 alkyl is optionally substituted, or
X and X1 taken together with the atom to which they are attached, form a C3-C7 cycloalkyl;
R7 is H, halogen, CrC6 alkyl, -C(=O)NR9R10, -C(O)(aryl), -C(=0)(heterocyclyl), -
C(=O)(heteroaryl)s -Y-(aryl), -Y-(heterocyclyl), -Y-(heteroaryl), -SR6a, -S-aryl, -S-(heteroaryl), -S~CrC6 alkyl, -SO-CrC6 alkyl, -SO2-Ci-C6 alkyl, -Y-NR9R10, -SCbNR9R!(), CO2R\ ~CHC-(CR4sR45)n-R46and-C(-NR42)NR37R43, wherein n is an integer ranging from 0 to 6 and wherein CrC6 allcyl, aryl, heterocycle and heteroaryl are each independently optionally substituted with 1 to 5 independently selected R38;
R9 and R10 are independently selected from H, Ci-C alkyl, -Y-(cycloalkyl), -Y-(C,-C6 heteroalkyl), -Y-(aryl), -Y-(heterocyclyl), -Y-(heteroaryl), -Y-O-Y'-O-R11, -Y1-CO2-Rn, Y-C(O)OR37 and -Y-O-R11, wherein said Cj-Ce alkyl,heteroalkyls cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally substituted with one or more independently selected R44, or R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted with 1 to 5 independently selected R44;
each R20 is independently selected from the group consisting of H, halo, -OR17 and -C(O)OR";
Y is a bond or is -(C(R")(H))r, wherein t is an integer from 1 to 6;
Y>is-(C(Rn)(E))V;and
Rl! at each occurrence is independently H or C1-C6 alkyl, wherein C1-C6 alkyl is optionally
substituted.
[01131 In a preferred embodiment of the compounds according to paragraph [0112], R1
is hydrogen or halogen.
[0114] In a preferred embodiment of the compounds according to paragraph [0112] to
[0113],R! is fluorine.
[0115] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0114], R7 is selected from the group consisting of H, -C(=O)MR.9R10, -Y-(aryl), -Y-
(heteroaryl) and -S-Cj-C6 alkyl, wherein said -Y-(aryl), -Y-(heteroaryl) and -S-CrC6 alkyl
are optionally substituted with 1 to 5 independently selected R3S.
24

WO 2006/010264 PCT/CA2005/OOI177
[0116} In a preferred embodiment of the compounds according to paragraphs [0112] to [0115], R7 is -C(=O)NR9R10, optionally substituted with one or more independently selected R44.
[0117] In a preferred embodiment of the compounds according to paragraphs [0112] to [0115], R? is -Y'(aryl), optionally substituted with 1 to 5 independently selected R38. [0118] In a preferred embodiment of the compounds according to paragraphs [0112] to [0115], R1 is -Y-(heteroaryl), optionally substituted with 1 to 5 independently selected R38. [0119] In a preferred embodiment of the compounds according to paragraphs [0112] to [0118], R38 is selected from the group consisting of halogen, -OR37, Ci-Csalkyl, -(CH2)n-(5 to 10 membered heterocyclyl), -(CH2)jNR39(CH2)nR36, -(CH2)JNR39(CH2)iNR36R39, -(CH2)n-hcteroaryJ, -C(O)NR36R39, -(CH2)nO(CH2),(5to 10 membered heterocyclyl) and -(CHZ^OCCHj^NR^R39, wherein n is an integer ranging from 0 to 6, j is an integer ranging from 0 to 2 , j is an integer ranging from 1 to 6 and wherein the alkyl, heteroaryl and heterocyclyl moieties of the foregoing R38 groups are optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -OH, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -(CH2)nNR36R39, Ci-C6 alkyl, C3-Ci0 cycloalkyl, ~(CH2)n(C6-Cio aryl), -(CH2)n(5-10 membered heterocyclyl), -(CH2)nO(CH2)iOR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6.. [0120] In a preferred embodiment of the compounds according to paragraphs [0112] to [0119], R38 is selected from the group consisting of-OR37, Ci-C6alkyl, -(CH2)n(5 to 10 membered heterocyclyl) and -(CH2)nO(CH2)j(5 to 10 membered heterocyclyl). [0121] In a preferred embodiment of the compounds according to paragraphs [0112] to [0120], R9 and R10 are independently selected from the group consisting of H, C\-C6 alkyl, -C,-C6 heteroalky!, -Y-(aryl), -Y-(heterocycIyl), -Y-(heteroaryl), -Y-O-R" and Y-C(O)OR37, wherein a C1-C6 alkyl, Cj-Co heteroalkyl, aryl, heterocyclcyl and heteroaiyl are each optionally substituted with 1 or more independently selected R44. [0122] In a preferred embodiment of the compounds according to paragraphs [0112] to [0121 ], R44 is selected from the group consisting of Cj-Ca alkyl, -OR37, -C(O)NR36R39 and -C(O)OR45.
[0123] In a preferred embodiment of the compounds according to paragraphs [0112] to [0122], R36 is selected from the grouip consisting of H, Q-C6 alkyl, -(CH2)nOR37 and -(CH2)n(heterocyclyl).
25

WO 2006/010264 PCT/CA2005/001177
[0124] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0123],R39isHorCi-C6alkyl.
[0125] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0124], R37 is H or CrC6 alkyl.
[0126] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0125], R20 is selected from the group consisting of H, halogen, -OR17 and -C(O)OR17.
[0127] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0126], R17 is H or CrC
[0128] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0127], R20 is halogen.
[0129] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0128],R20isClorF.
[0130] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0129], R6a is -(CZ^Varyl.
[0131] In a preferred embodiment of the compounds according to paragraph [0112] to
[0114], R7 is selected from the group consisting of H, halogen, Ct-C6 alkyl, -C0NR9R10, -
SO2NH2, -SOJNRV0, -Y-heterocyclyl, -Y-heteroaryl, -S-aryt, -S-C,-C6 alkyl, -SO-CrC6
alkyl, or -SO2-Ci-C6 alkyl, wherein C1-C6 alkyl is unsubstituted or is substituted with one or
two of hydroxy or halogen, and the heterocyclyl, and heteroaryl are unsubstituted or are
substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0132] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0114], R7 is selected from the group consisting of H, halogen, CrQ alkyl, -SC^NR'R10, -
C(=O)(heterocyclyl), -Y-(heterocyclyl), -Y-(heteroaryl), -S-aryl, -S-C]-C6 alkyl, -SO-Ci-Q
alkyl, or -SO2-Ci-Q alkyl, wherein d-Cs alkyl is unsubstituted or is substituted with one or
two of hydroxy or halogen, and the heterocyclyl, and heteroaryl are unsubstituted or are
substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0133] In a preferred embodiment of the compounds according to paragraph [0116], R9
and R10 are independently selected from the group consisting of H, CrC& alkyl, C1-C6
heteroalkyl, -Y-O-R11, -Y-(heterocycle), -Y-CO2-R11, -Y-(aryl) and -Y-(heteroaryl),
wherein C1-C6 alkyl is unsubstituted or is substituted with one or two of hydroxy or
halogen, and the heterocyclyl, aryl and heteroaryl are unsubstituted or are substituted with
one or two of alkoxy, alkyl, or haloalkyl.
[0134] In a preferred embodiment of the compounds according to paragraph [0116], R9
and R!0 are taken together with the nitrogen to which they are attached to form a
26

WO 2006/010264 PCT/CA2005/001177
27
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstituted or is substituted with one or two of atkoxy, alkyl, or haloalkyl. [0135] In a preferred embodiment of the compounds according to paragraph [0116], NR9R10 is selected from:

WO 2006/010264 PCT/CA2005/001177
[0136] In a preferred embodiment of the compounds according to paragraph [0118] R7
is unsubstituted heteroaryl.
[0137] In a preferred embodiment of the compounds according to paragraph [0136], R7
is thiazolyl, pyridinyl, pyrimidinyl, and imidazolyl, each of which is preferably
unsubstituted or is substituted with one or two of alkoxy, or alkyl.
[0138] In a preferred embodiment of the compounds according to paragraphs [0131] to
[0132], R7 is C1-C6 alkyl, unsubstituted or substituted with hydroxy.
[0139] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0138], X and X1 are both H.
[0140] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0139], R17 is selected from the group consisting of H and C1-C6 alkyl.
[0141] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0140], R38 is selected from the group consisting of-OR37, C|-C6 alkyl and -(CH2)n(5 to 10
membered heterocylic), wherein n is an integer ranging from 0 to 6.
[0142] In a preferred embodiment of the compounds according to paragraphs [0112] to
[0141], RJ? is selected from the group consisting of H and C1-C6 alkyl.
[0143] In a preferred embodiment of the compounds according to paragraph [0040], the
compounds are represented by the formula A-2:

WO 2006/010264 PCT/CA20O5/0O1177
heteroaryl are each independently optionally substituted with 1 to 5 independently
selected R38; R9 and R10 are independently selected from the group consisting of H, Ci-Q alkyl. -Y-
(cycloalkyi), -Y-(aryl). -Y-(heterocyclyl), -Y-(heteroaryl), -Y-O-Y'-O-R11, -Y1-
COrRU and -Y-O-R1', wherein Ci-C6 alkyl, cycloalkyl, aryl, heterocycle, and
heteroaryl are each optionally substituted with one or more independently selected
R^or R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted; Y is a bond or is -(C(Rn)(H)V> wherein t is an integer from 1 to 6; Y, is-(C(RM)(H)>, and
R" at each occurrence is independently H or Q-Ce alkyl, wherein CrC6 alkyl is optionally substituted.
(0144] In a preferred embodiment of the compounds according to paragraph [0143], Rl is hydrogen or halogen.
[0145] In a preferred embodiment of the compounds according to paragraphs [0143] to 1.0144], RWs fluorine.
[0146] In a preferred embodiment of the compounds according to paragraphs [0143] to [0145], R4 is selected from the group consisting of H and halogen, [0147] In a preferred embodiment of the compounds according to paragraphs [0143] to [0146], R4 is fluorine.
[0148] In a preferred embodiment of the compounds according to paragraphs [0143] to [0147], R7 is selected ftom the group consisting of H, halogen, C1-C6 alkyl, -C(=O)NR9R10, -SO2NH2, -SO2NR9R10, -Y-hetcrocydyl -Y-heteroaryl, -S-aryl, -S-Cl-C6 alkyl, -SO-C1-C6 alkyl and -SO2-C1-C6 alkyl, wherein CI-C6 alkyl, heterocyclyl, heteroaryl and aryl are each optionally substituted with 1 to 5 independently selected R38. [0149] In a preferred embodiment of the compounds according tc paragraphs [0143] to [0147], R7 is selected from the group consisting of H, halogen^ C1-C6 alkyl, -C(=O)NR9R10, -SO2NH2, -SO2NR9R10, -Y-heterocyclyl -Y-heteroaryl, -S-aryl, -S-Cl-C6 alkyl, -SO-C1-C6 alkyl and -SO2-C1-C6 alkyl, wherein C1-C6 alkyl is unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocyclyl, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, haloalkyi or (CH2)jNR39(CI-I2)nO(CH2)iOR37.
29

WO 2006/010264 PCT/CA2005/001177
£0150] In apreferred embodiment of the compounds according to paragraphs [0143] to
[0147], R7 is selected from the group consisting of H, halogen, C1-C6 alkyl, -SO2NR9R10,
-C(=O)(heterocyclyl), -Y-(heterocyclyl), -Y-(heteroaryl), -S-aryl, -S-C1-C6 alkyl, -SO-C1-
C6 allcyl, or -SO2-C1-C6 alkyl, wherein C1-C6 alkyl is unsubstituted or is substituted with
one or two of hydroxy or halogen, and the heterocyclyl, and heteroaryl are unsubstituted or
are substituted with one or two of alkoxy, alkyl, haloalkyl or
(CH2)jNR39(CH2)nO(CH2)iOR37.
[0151] In a preferred embodiment of the compounds according to paragraphs [0143] to
[0150], R7 is selected from the group consisting of C1-C6 alkyl, -C(=O)NR9R10, -Y-
(heterocyclyl, -Y-(heteroaryl), -S-C1-C6 alkyl and -SO-C1-C6 alkyl, wherein C1-C6 alky!
is unsubstituted or is substituted with one or two of hydroxy or halogen, and the
heterocyclyl, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy,
alkyl, haloalkyl or (CH2)jNR39(CH2)nO(CH2)iOR37.
[0152] In a preferred embodiment of the compounds according to paragraphs [0143] to
[01Sl],R7isCONR9R10.
[0153] In a preferred embodiment of the compounds according to paragraph [0152], R9
and RIO are independently selected from the group consisting of H, C1-C6 alkyl, -Y-O
Rl 1, -Y-(heterocycle), -Y1-CO2-R11 and -Y-(aryl), wherein the alkyl, heterocyclyl and
aryl moieties of the foregoing R9 and R10 groups are optionally substituted with 1 or more
substituents independently selected from R44.
[0154] In a preferred embodiment of the compounds according to paragraphs [0152] to
[0153], R9 and R10 are independently selected from the group consisting of H, C1-C6
alkyl, -Y-O-Rll, -Y-(heterocycle), -Y1-CO2-R11 and -Y-(aryl), wherein C1-C6 alkyl is
unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocyclyl,
and aryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, haloalkyl or
(CH2)jNR39(CH2)nO(CH2)iOR37.
[0155] In a preferred embodiment of the compounds according to paragraph [0152], R9
and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyi ring or a heteroaryl ring, wherein said ring is optionally substituted.
[0156] In a preferred embodiment of the compounds according to paragraph [0155], R9
and R10 are taken together with the nitrogen to which they are attached to form a
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl ring, wherein said
ring is unsubstituted or is substituted with one or two of alkoxy,. alkyl, or haloalkyl.
30

WO 2006/010264 PCT/CA20O5/OO1177
[0157] In a preferred embodiment of the compounds according to paragraph [0152], NR9R10 is selected from the group consisting of:

[0158] In a preferred embodiment of the compounds according to paragraph [0040], the compounds are represented by the formula A-3:

and pharmaceuticslly acceptable salts and complexes thereof, wherein
R7 is selected from the group consisting of H, -Y-(aryl) and -Y-(heteroaryl), wherein -Y-
(aryl) and -Y-(heteroaryl) are optionally substituted with 1 to 5 independently
selected R38; R1 is selected from the group consisting of hydrogen, halo, Q-Q alkyl. C2-C6 alkenyl and
C2-C6 alkynyl, wherein C1-C6 alkyl, Cz-C^ alkenyl and C2-Q alkynyl are optionally
substituted; R12 is selected from the group consisting of H, C\-Ce alkyl, -O(Ci-C
wherein C1-C6 alkyl and aryl are optionally substituted; Y is a bond or is -(C(RH)(H))r, wherein t is an integer from 1 to 6; Rn is H or Ci-Ce alkyl, wherein Ci-Ce alkyl is optionally substituted; and each R20 is independently selected from the group consisting of H and halogen. [0159] In a preferred embodiment of the compounds according to paragraph [0158], R1 is hydrogen or halogen.
[0160] In a preferred embodiment of the compounds according to paragraphs [0158] to [0159], R! is fluorine.
[0161] In a preferred embodiment of the compounds according to paragraphs [0158] to [0160], R12 is unsubstituted Cj-C3 alkyl or unsubstituted -Y-phenyl.
31

WO 2006/010264 PCT/CA2U05/001177
[0162] In apreferred embodiment of the compounds according to paragraphs [0158] to
[016i],R20isCl.
[0163] In a preferred embodiment of the compounds according to paragraph [0040], the
compounds are represented by the formula A-4:

and pharmaceutically acceptable salts and complexes thereof, wherein
Z is O or S;
X and X! are independently selected from the group consisting of H, Ci-Cg alkyl, halo,
cyano and nitro, wherein Cj-Ce alkyl is optionally substituted; R1, R2, R3, R4, R1 and R6 are independently selected from the group consisting of hydrogen,
halo, C,-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and NR17R1S, wherein CrC6 alkyl,
Cz-C(, alkenyl and C2-C6 alkynyl are optionally substituted; R17 and R18 are independently Ci-C6alfcyl; Q is O, S, NH, N(Ci-C6 alkyl), or N-Y-(aryl); DisCR",orN; L is N, or CR, wherein R is selected from the group consisting of H, halo, -CN, CrQ alkyl,
C2-G5 alkenyl and C2-C6 alkynyl, wherein Ci-C6 alkyl, C2-C6 alkenyl, and C2-C.6
alkynyl are optionally substituted; and
R13 is heterocyclyl or heteroaryl, wherein heterocyclyi and heteroaryl are optionally substituted with 1 to 5 independently selected R38; Y is a bond or is -(C(Rn)(H))r, wherein t is an integer from 1 to 6; and R!1 at each occurrence is independently H or C\-C$ alkyl, wherein Ci-Cg alkyl is optionally
substituted.
[0164] In a preferred embodiment of the compounds according to paragraph [0163], X and X1 are both hydrogen.
[0165] In a preferred embodiment of the compounds according to paragraphs [0163] to [0i64], R1, R2, R3 and R4 are independently H or halogen.
[0166] In a preferred embodiment of the compounds according to paragraphs [0163] to [0165], R1 is hydrogen or halogen.
32

WO 2006/010264 PCT/CA2O05/O01177
[0167] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0166], R1 is fluorine or chlorine.
[0168] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0167], R4 is hydrogen or halogen.
[0169] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0168], R4 is fluorine or chlorine.
[0170] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0169], R2, R\ R5, and R6 are each hydrogen.
[0171] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0170], Q is selected from the group consisting of S, N(Ci-C6 alky!) and N-Y-(aryl).
[0172] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0171], Q is S.
[0173] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0172],DisCRu.
[0174] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0173], Rl 1 isH.
[0175] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0174],LisCHorN.
[0176] In a preferred embodiment of the compounds according to paragraphs [0163] to
[0175],LisCH.
rfl177l In s» nrpfprrprl pmhnHimpnt nf ihp mmnnimHe arrdrAino tn nnrnoranfic Ffii/v^i-
J3

WO 2006/010264 PCT/CA2005/00117?

and pharmaceutically acceptable salts and complexes thereof, wherein
R7 is selected from the group consisting of H, -C(O)NR42R43, -Y-(aryl), -Y-(heteroaryl), -
C(0)-(C3-Cio cycloalkyl), -C(O)-(heterocyclyl), -C(O)-(C6-Ci0 aryl) and -C(O)-
(heteroaryl), wherein the aforementioned R7 groups other than H are optionally
substituted with 1 to 5 independently selected R38; R4 is selected from the group consisting of H and halogen; and T is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl and
arylalkyl, each of which is optionally substituted with 1 to 3 independently selected R20; [0182] In a preferred embodiment of the compounds according to paragraph [0181], R7 is selected from the group consisting of H, C(O)NR42R43 and -Y-(heteroaryl), wherein -Y-(heteroaryl) is optionally substituted with ) to 5 independently selected R38; [0183] In a preferred embodiment of the compounds according to paragraphs [0181] to [0182],R7isC(O)NR42R43;
[0184] In a preferred embodiment of the compounds according to paragraphs [0181] to [0183], R42 and R43 taken together with the nitrogen to which they are attached form a C5-C9 heterocyclyl ring, wherein said ring is optionally substituted with 1 to 5 independently selected R44 substituents, with the proviso that R42 and R43 are not both bonded to the nitrogen directly through and oxygen.
[0185] In a preferred embodiment of the compounds according to paragraphs [0181 ] to [0184], R4 is halogen.
[0186] In a preferred embodiment of the compounds according to paragraphs [0181] to [0185], R4 is fluorine.
[0187] In a preferred embodiment of the compounds according to paragraph [0040], the compounds are represented by the formula A-6:
34

WO 2006/010264 PCT/C A2005/001177

and pharmaceutically acceptable salts and complexes thereof, wherein
R1 is selected from the group consisting of hydrogen, halo, Ci-Q alkyl, C2-C6 alkenyl or C2-Q; alkynyl, wherein Q-C6 allcyl, C2-C6 alkeny! and C2-C6 alkynyl are optionally substituted;
R7 is selected from the group consisting of H, halogen, Ci~C6 alkyl, -C(O)NR9R10, -
C(=O)(aryl), -C(=O)(heterocyclyl), -C(=O)(heteroaryl), -Y-(aryl), -Y-(heterocyclyl), -Y-(heteroaryl), -SR6a, -S-aryl, -S-(heteroaryl), -S-Ci-C6 alkyl, -SO-Ci-C6 alkyl, -SCVCi-Ce alkyl, -Y-NR9R10, -SO2NR9R10, CO2R9, -CHC-(CR45R45)n-R46 and -C(=NR42)NR37R43, wherein n is an integer ranging from 0 to 6 and wherein CpCg alkyl, aryl, heterocycle and heteroaryl are each independently optionally substituted with 1 to 5 independently selected R38;
R9 and R10 are independently selected from the group consisting of H, Cj-C$ alkyl, -Y-(cycloalkyl), -Y-(CrC6heteroalkyl), -Y-(aryl), -Y-{heterocyclyl), -Y-(heteroaryl), -Y-O-Y'-O-R11, -Y'-CO2-Rn, Y-C(O)OR37 and -Y-O-R11, wherein said C,-C6 alkyl,heteroalkyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally substituted with one or more independently selected R4\ or
R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9 heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted with 1 to 5 independently selected R44;
each R20 is independently selected from the group consisting of H, halo, -OR17 and -C(O)OR17;
Y is a bond or is -(C(R! l)(H))r, wherein t is an integer from 1 to 6;
YMs-(CCRn)(H)X-;and
R11 at each occurrence is independently H or C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted.
[0188] In a preferred embodiment of the compounds according to paragraph [0187], R7
is selected from the group consisting of H, C(O)NR9R10 and -Y-(heteroaryl), wherein -Y-
(heteroaryi) is optionally substituted with 1 to 5 independently selected R38;
35

WO 2006/010264 PCT/CA2005/OO1177
[0189] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0188],R7isC(O)NR9R10;
[0190] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0189], R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring, wherein said ring is optionally substituted with 1 to 5 independently
selected R44 substituents.
[0191] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0190], R' is -Y-(heteroaryl), wherein said -Y-(heteroaryl) is optionally substituted with 1 to
5 independently selected R38.
[0192] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0191], R7 is -Y-(heteroaryl), wherein said -Y-(heteroaryl) is optionally substituted with one
Ci-Cc alkyi.
[0193] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0192], R! is halogen.
[0194] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0193], R'is fluorine.
[0195] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0194], R!7 is selected from the group consisting of H and Ci-Ce alkyi.
[0196] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0195], R38 is selected from the group consisting of-OR37, C-C6 alky! and -{CH2)n(5 to 10
membered heterocylic), wherein n is an integer ranging from 0 to 6.
[0197] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0196], Rj7 is selected from the group consisting of H and Ci-Ct alkyi.
[0198] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0197], each R20 is independently selected from the group consisting of H, halogen and -O-
(Ci-C6)alkyl.
[0199] In a preferred embodiment of the compounds according to paragraphs [0187] to
[0198], two R20 are H and the third R20 is selected from the group consisting of H, halogen
and-O-(Ci-C6 alkyi).
[0200] In a second aspect, the invention comprises compounds of formula (B), which
are inhibitors of VEGF receptor signaling and fIGF receptor signaling:
36

WO 2006/010264 PCT/CA2OO5/001177

and pharmaceutically acceptable salts and complexes thereof, wherein T is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with 1 to 3 R20;
each R20 is independently selected from the group consisting of-H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR17, -OCF3, -NRl7R18, -S(0)o.2R!7, -S(O)2NR17R17, -C(O)OR17, -C(O)NRI7R17, -N(R17)SO2R17, -N{R17)C(O)R17, -N(R17)C(O)OR17, -C(O)R17, -C(O)SR17, C,-C4 alkoxy, CrC4 alkylthio, -O(CH2)naryl, -O(CH2)nheteroaryl, -(CH2)o-5(aryl), -(CH2)0.5(heteroaryl), CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkyny], ~CH2(CH2)o-4-T2, an optionally substituted CM alkylcarbonyl, C14 alkoxy, an amino optionally substituted by C1-4 alkyl optionally substituted by CM alkoxy and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMe, -OEt, -NH2, -NHMe, -NMe?, -NHEt and -NEt2, and wherein the aryl, heteroaryl, C\-Ce alkyl, C2-Cs alkenyl, and C2-Ce alkynyl are optionally substituted; W is selected from the group consisting of O, S and NH; Z is selected from the group consisting of O, or S and NH; X and X1 are independently selected from the group consisting of H, CrC6 alkyl, halo,
cyano, or nitro, wherein Ct-C6 alkyl is optionally substituted, or
X and X1 taken together with the atom to which they are attached, form a C3-C7 cycloalkyl; R1, R2, RJ and R4 are independently selected from the group consisting of hydrogen, halo, trihalomethyl, -CN, -NO2, -NH2, -ORr/, -NR17R18, -C(O)OR17, -C(O)Ri7, C1-C4 alkoxy, C1-C4 alkylthio, Q-Q alkyl, C2-Ce alkenyl or C2-C6 alkynyl, wherein Q-Cg alkyl, C2-C6 alkenyl and C2-C6 alkynyl are optionally substituted; R17 is selected from the group consisting of H and R18;
R1S is selected from the group consisting of a Ci-Cg alkyl, an aryl, an aryl(CrC6 alkyl), a heterocyclyl and a heterocyclyl(Ci-C6 alkyl), each of which is optionally substituted, or
37

WO 2006/010264 PCT/CA2OO5/OO1177
R17 and R's, taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, the optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heleroatom selected from the group consisting of N, 0, S and P; R16 is selected from the group consisting of-H, -CN, -(CH2)o-5(aryl), -(CH2)o.s(heteroaryi), C,-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2(CH2)0-4-T2, an optionally substituted Cu alkylcarbonyl, and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMe, -OEt, -NH2, -NHMe, -NMez, -NHEt and -NEt2j and wherein the aryl, heteroaryl, Ci-Ce alkyl, Cj-Cg alkenyl, and C2-C6 alkynyl are optionally substituted;
D is selected from the group consisting of CH2, O, S, NH, N-(CrCo alkyl), or N-Y-(aryl), -N-OMe, -NCH2OMe and -N-Bn; Q is selected from the group consisting of C-E and N; L is N, or CR, wherein R is selected from the group consisting of-H, halo, -CN, Ci-Cg
alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein Ci-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted; and E is selected from the group consisting of E1, E2 and E3; wherein E1 is selected from the group consisting of-H, halogen, nitro, azido, C]-Cg alkyl, C3-C10 cycloalkyl, -C(O)NR42R43, -Y-NR42R43, -NR42C(=O)R43, -SO2R42, -SO2NR42R43, -NR37SO2R42, -NR37SO2NR42R43, -C(=N-OR42)R43, -C(=NR42)R43, -NR37C(=NR42)R43, ~C(=NR42)NR37R43, -NR37C(=NR42)NR37R43, -C(O)R42, -CO2R42, -C(O)(heterocyclyl), -C(O)(C6-C,0 aryl), -C(O)(heteroaryl), -Y-(C6-Ci0 aryl), -Y-(heteroaiyl), -Y-(5-10 membered heterocyclic), -NR5aR6b, -NR6aSO2R6b5 -NR6aC(O)Rdb, -OC(O)R6b, -NR6aC(O)OR6b, -OC(O)NR6aR6b,-OR6a, -SR6a, -S(O)R6\ -SO2R6a, -SO3R6a, -SO2NR6aR6b, -SO2NR42R43, -COR6a, -CO2R6a, -CONR6aR6b, -(Cr C4)fluoroalkyl, -(Ci-C4)fiuoroalkoxy, -(CZ3Z4)-,CN, wherein n is an integer ranging from 0 to 6, and the aforementioned E1 groups other than -H and halogen are optionally substituted by 1 to 5 independently selected R38, or E1 is selected from a moiety selected from the group consisting of -(CZ3Z4)a-aryl, -(CZ3Z4)a-heterocycle, (C2-C
38

WO 2006/010264 PCT/CA2005/001177
each R38 is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -NR36R39, -OR37, -SO2NR36R39, CrC6 alkyl, -(CH2)JO(CH2),NR36R39, -(CH2)nO(CH2)iOR371 -(CH2)nOR37, -SCO^d-Ce alkyl), -(CH2)n(C6-C10 aryl), -(Cn2UC5-C]0 heteroaryl), -(CH2)n(5-10 membered heterocyclyl); -C(O)(CH2)a(C6-C10 aryl), -(CH^OCCII^Q-C,,, atyl), -(CH2),,O(CH2)i(5-10 membered heterocyclyl), -C(O)(CH2)n(5-10 membered heterocyclyl), -(CH2)jNR39(CH2),NR36R39, -(CH2)jNR39CH2C(O)NR36R395 -(CH2)JNR39(CH2)iNR37C(O)R40, -(CH2)jNR39(CH2)nO(CH2)iOR37) -(CH2)jNR39(CH2),S(O)j(C,-C6 alkyl), -(CH^NR^CH^R36, -SO2(CH2)n(C6-CI0 aryl), -SO2(CH2)n(5-10 membered heterocyclyl), -(CH2)nNR36R3S, -NR37SO2NR3(iR39, SO2R36, C2-C6 alkenyl, C3-C10 cycloalkyl and C;-C6 alkylamino, wherein j is an integer ranging from 0 to 2, n is an integer ranging from 0 to 6, i is an integer ranging from 0 to 6, the -(CH2),- and -(CH2)n- moieties of the foregoing R38 groups optionally include a carbon-carbon double or triple bond where n is an integer between 2 and 6, and the alkyl, aryl, heteroaryl and heterocyclyl moieties of the foregoing R3S groups are optionally substituted by one or more substituents independently selected from halo, cyano, nitro, trifluorornethyl, azido, -OH, -C(O)R40, -C(O)OR40, -OC(O)R405 -OC(0)OR4°, -NR3(5C(O)R3?, -C(O)NR36R39, -{CH2)nNR36R39, CrC6 alkyl, C3-C10 cycloalkyl, -(CH2)n(C6-Cio aryl), -(CH2)n(5-10 membered heterocyclyl), -(CH2)nO(CH2)jOR37, and -(CH2)nOR37, wherein n is an integer langing from 0 to 6 and i is an integer ranging from 2 to 6;
each R42 and R43 is independently selected from the group consisting of H, Cj-Q alkyl, Q-C6 heteroalkyl, -Y-(C3-C!0 cycloalkyl), -Y-(C5-Ci0 aryl), -Y-(C6-Ci0 heteroaryl), -Y-(5-10 membered heterocyclic), -Y-O-Y'-OR37, -Y'-CO2-R37, and -Y-OR37, wherein the alkyl. heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic moieties of the foregoing R42 and R43 groups are optionally substituted by 1 or more substituents independently selected from R44, wherein
Y is a bond or is -(C(R37)(H))n,
n is an integer ranging from 1 to 6, and
Y1is-(C(R37)(H))n,or
R42 and R43 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted by 1
39

WO 2006/010264 PCT/CA2005/001177
to 5 R44 substituents, with the proviso that R42 and R43 are not both bonded to the nitrogen directly through an oxygen;
each R44 is independently selected from the group consisting of halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, -C(O)R40, -C(O)OR40, -OC(O)R40, -0C(O)0R40, -NR36C(O)R39, -C(O)NR36R39, -NR36R39, -OR37, -SCbNR36R39, -SO2R36, -NR36SO2R39, -NR36SO2NR37R41, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, -C,-C6 alkylaraino, -(CH2)jO(CH2)iNR36R39, -CCH2)nO(CH2)iOR37, -(CH2)nOR37, -S(O)j(C,-C6 alkyl), -(CH2)n(C6-C10 aryl), -(CH2)n(5-10 membered heterocyclic), -C(0)(CH2)n(C6-C,o aryl), -{CH2)nO(CH2)j(C6.C,0 aryl), -(CH2)nO(CH2)i(5 to 10 membered heterocyciic), -C(O)(CH2)n(5 to 10 membered heterocyclic), ~(CH2)jNR39(CH2),NR36R39, -(CH2)jNR39CH2C(O)NR36R39, -(CH2)jNR39(CH2),NR37C(O)R40, -(CH2)jNR39(CH2)nO(CH2)iOR37, -(CH2)jNR39(CH2)iS(O)j(C1-C6 alkyl), -(CH2)jNR39(CH2)nR36, -SO2(CH2)n(C6-C10 aryl), and -SO2(CH2)n(5 to 10 membered heterocyclic) wherein, j is an integer from 0 to 2, n is an integer from 0 to 6 and i is an integer ranging from 2 to 6, the -(CH2)i-and -(CH2)ni- moieties of the foregoing R44 groups optionally include a carbon-carbon double or triple bond wherein n is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R44 groups are optionally substituted by 1 or more substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -OH, -C(O)R40, -C(0)OR4°, -OC(O)R4Q, -OC(O)OR40,-
40

WO 2006/010264 PCT/CA2005/001177
CO(O)R40, -OC(O)OR40, -NR37C(O)R41, -C(O)NR37R41, -NR37R4t, -C,-C6 alkyl, -(CH2)n(C6-Cio aryl), -(CH2)n(5 to 10 membered heterocyclic), -(CH2)r.O(CH2)iOR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, with the proviso that when R36 and R39 are both attached to the same nitrogen, then Rj6 and R39 are not both bonded to the nitrogen directly through an oxygen;
each R37 and R4! is independently selected from the group consisting of H, OR36, CrC6
alkyl and C3-CIQ cycloalkyl;
each Roa and Rob is independently selected from the group consisting of hydrogen, -(CZ'ZV(C3-C6)cycIoalkyl, -(CZsZ6)u-(C5-C6)cycloa!keny!, -(CZ5Z6)u-aryl, -(CZ^u-heterocycle, (C2-C6)alkenyl, and (Ci-Ce)alkyl, which is optionally substituted with 1 to 3 independently selected Y3 groups, where u is 0,1, 2, or 3. and wherein when u is 2 or 3, the CZSZ° units may be the same or different, or
R03 and R6b taken together with adjacent atoms can form a heterocycle;
each Z3, Z4, Z5 and if is independently selected from the group consisting of H, F and (C|-C6)alkyl, or
each Z3 and Z4, or Z5 and Z6 are selected together to form a carbocycle, or
two 'V groups on adjacent carbon atoms are selected together to optionally form a carbocycle;
each Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, azido, -C(O)Z7, -0C(0)NH2, -OC(O) NHZ7, -OC(O)NZ7Z8, -NHC(O)Z7, -NHC(O)NH2, -NHC(0)NHZ7, -NHC(O)NZ7Z8, -C(O)OH, -C(O)OZ7, -C(O)NH2: -C(O)NHZ7,-C(O)NZ7Z!i! -P(O)3H2, -P(O)3(Z7)2, -S(O)2fi -S{O)Z7, -S(O)2Z75 -S(O)jZ7, -Z7, -OZ7, -OH, -NH2: -NHZ7r ¦• MZ7Z8: -C(-Nl-i)NH25-C(-NOH)NH2, -N-morphoiino, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, (C2-C6)haioalkenyl, (C2-C6)haioalkynyl,"(C1-C6)haloalkoxy, -(CZ9Z10)rNH2, -(CZ9Z10)rNHZ3, -(CZ9Z10)rNZ7Z3, -X6(CZ9Z10)r(C3-Cs)cycloalkyl, -X6(CZ9Z10)r(C5-C8)cycloalkenyl, -X6(CZ9Z!0)r-aryl and -X6(CZ9ZJ0)r heterocycle, wherein
r is 1,2. 3 or 4;
X6 is selected from the group consisting of O, S, NH, -C(O)-, -C(O)NH-, -C(O)O-, -S(O)-, -S(O)2- and -S(O)3-;
Z7 and 7} are independently selected from the group consisting of an alkyl of 1 to 12 carbon atoms, an alkenyl of 2 to 12 carbon atoms, an alkynyl of 2 to 12 carbon atoms, a
41

WO 2006/010264 PCT/CA2005/001177
cycloalkyl of 3 to 8 carbon atoms, a cycloalkenyl of 5 to 8 carbon atoms, an aryl of 6 to 14 carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7 to 15 carbon atoms, and a heteroaralkyl of 5 to 14 ring atoms, or
Z7 and Z8 together may optionally form a heterocycle;
Z9 and Z!o are independently selected from the group consisting of H, F, a (CrC[2)alkyl, a (C6-Ci4)aryl, a (C5-Ci4)heteroaryl, a (C7-Cis)aralkyl and a (C5-Ci4)heteroaralkyl, or
Z9 and Z10 are taken together form a carbocycle, or
two Z9 groups on adjacent carbon atoms are taken together to form a carbocycle; or
any two Y2 or Y3 groups attached to adjacent carbon atoms may be taken together to be -O[C(Z9)(Z10)]rO or -O[C(Z9XZI0)]rH, or
any two Y2 or Y3 groups attached to the same or adjacent carbon atoms may be selected together to form a carbocycle or heterocycle; and wherein
any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not attached to a halogen, SO or SO2 group or to a N, O or S atom optionally bears on said group a substituent selected from hydroxy, halogen, (CrC4)alkyl> (CrC4)alkoxy and an -N[(Ci-C4)alkyl][(C,-C4)alkyl];
E2 is -C=CH or -OC-(CR4SR45)n~R46;
R45 is independently selected from the group consisting of H, a (Ci-C6)alkyl and a (C3-C8)cycloalkyl;
R46 is selected from the group consisting of heterocyclyl, -N(R47)-C(O)-N(R47)(R48), -N(R47)-C(S)-N(R47)(R48), -N(R47)-C(O)-0R48, -N(R47)-C(O)-(CH2)n-R48, -N(R47)-SO2R47, -(CH2)nNR47R48, -(CH2)nOR4S, -(CH2)nSR49, -(CH2)nS(O)R49, -(CH2)nS(O)2R49, -OC(O)R49, -OC(O)OR49, -C(O)NR47R48, heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (CrC6)alkoxy, -NO2, (CrC6)alkyl, -CN, -SO2R50 and -(CH2)nNR50R51, and aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, (CrC6)alkyl, -CN, ~SO2R50 and -(CH2)nNR5OR51;
R47 and R48 are independently selected from the group consisting of H, (Ci-Q)alkyl, (C3-C8)cycloalkyl( heterocyclyl, -(CH2)nNR5ORsl, -
42

WO 2006/010264 PCT7CA20O5/O0J177
optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (CrC6)alkoxy, -NO2, (C,-Chalky], -CN, -(CH2)nOR49, -(CH2)nheterocyclyl, -(CH2)nheteroaryl, -SO2RS0 and -(CH2)nNR50R51, or
R47 and R48, together with the atom to which they are attached, form a 3-8 membered ring;
R49 is selected from the group consisting of (C|-C6)alkyl, (Ca-C^cycloalkyl,
heterocyclyJ(Ci-C6)alkylene, aryl(CrC6)alkylene wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2l (Ci-C6)alkyl, -CN, -SO2R50 and -(CH2)nNR50R51, heteroaryl(Ci-Co)alkylene wherein the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, (Ci-Cs)alkyl, CN, -SO3RS0 and -(CH2)nNR50R5\ aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)a!koxy, -NO2, (C;-C6ialky!, -CN, -SOzR* and -(CH2)nNR50R51, and heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, (Ci-C6)alkyL -CN, -SO2RS0 and -(CH2)nNR50R51;
R5u and R51 are- independently selected from the group consisting of H, (Ci-C^alkyl, (CV C»)cycloa!kyl and -C(O)R45, or
R'^° and R*1, together with the atom tc which they are attached, form a 3-8 membered ring; and
E3 is the group defined by -(Zu)-(Zl2)m-(Zn)mh wherein
Z1! is heterocyclyl or heterocyclylene;
Z12 is selected from the group consisting of OC(O), OC(S) and C(O):
Z13 is selected from the group consisting of heterocyclyl, aralkyl, N(H)R52, (Ci-C3)alk>'i, -OR52, halo, S(O)2R56, (Ci-C3)hydroxyalkyl and (Ci-C3)haloalkyl;
rn isOor 3,
ml is 0 or 1;
R52 is selected from the group consisting of H, -(CH2)qS(O)2R54, R55NR5:iR53, (CrC3)alkyl, -(CHaJqOR53, -C(O)R54 and -C(O)OR53;
qisO, 1,2,3 or 4;
R53 is (C,-C3)alkyl;
R54 is (Ci-C3)alkyl or N(H)R53;
R55 is (C,-C6) alkyl; and
R56 is selected from the group consisting of NH2, (Ci-C3)alkyl and OR52.
43

WO 2006/1)10264 PCT/CA2O05/001177
[0201] In a preferred embodiment of the compounds according to paragraph [0200], the compounds are represented by the formula B-0:

and pharmaceutically acceptable salts and complexes thereof, wherein
Z is O or S;
X and X'are independently selected from the group consisting of H, Ci-C$ alkyl, halo,
cyano, or nitro, wherein C|-C6 alkyl is optionally substituted; R1, R2, R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen,
halo. Ci-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, wherein Ci-C5 alkyl, C2-C6
alkenyl and C2-C6 alkynyl are optionally substituted; Q is O, S, NH, N(C|-C6 alkyl), or N-Y-(aryl); L is N, or CR, wherein R is halo, -CN, Q-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl,
wherein Ci-Ce alkyl, C2-C& alkenyl, and C2-C6 allcynyl are optionally substituted;
and R7 is selected from the group consisting of H, halogen, Ci-Q alkyl, -C(=O)NR9R10, -
C(=O)(aryl), -C(=0)(heterocyclyl), -C(=O)(heteroaryt), -Y-(aryl), -Y-(heterocyclyl),
-Y-(heteroaryl), -Y-NR9R10, -SO2NR9R10 and CO2R9, wherein CrC6 alkyl, aryl,
heterocyclyl and heteroaryl are each optionally substituted; R9 and R10 are independently selected from the group consisting of H, C1-C6 alkyl, -Y-
(cycloalkyl), -Y-(aryl), -Y-(heterocyclyl), -Y-(heteroaryl), -Y-O-Y'-O-R11, -Y1-
CO2-R11, and -Y-O-R11, wherein C1-C6 alkyl, cycloalkyl, aryl, heterocyclyl, and
heteroaryl are each optionally substituted, or Ry and Ri0 are taken together with the nitrogen to which they are attached to form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted; Rs is selected from the group consisting of H, halo and C\-C& alkyl, wherein C1-C6 alkyl is
optionally substituted:
Y is a bond or is -(C(R1!)(H))r, wherein t is an integer from 1 to 6; Y1 is -(C(Rn)(H))t-, and
44

WO 2006/010264 PCT/CA20U5/001177
Rl! at each occurrence is independently H or Ci-C6 alkyl, wherein C1-C6 alkyl is optionally
substituted.
[0202] In a preferred embodiment of the compounds according to paragraph [0201], X and X1 are both hydrogen.
[0203] In a preferred embodiment of the compounds according to paragraphs [0201] to [0202], R1 is hydrogen or halogen.
[0204] In a preferred embodiment of the compounds according to paragraphs [0201] to [0203], R1 is fluorine.
[0205] In a preferred embodiment of the compounds according to paragraphs [0201] to [0204], R4 is hydrogen or halogen.
[0206] In a preferred embodiment of the compounds according to paragraphs [0201] to [0205] R4 is fluorine.
[0207] In a preferred embodiment of the compounds according to paragraphs [0201] to [0206], R2, R3, R5, and R6 are each hydrogen.
[0208] In a preferred embodiment of the compounds according to paragraphs [0201] to [0207], Q is S, N(CrC6 alkyl), or N-Y-(aryl).
[0209] In a preferred embodiment of the compounds according to paragraphs [0201] to [0208], L is CH or N.
[0210] In a preferred embodiment of the compounds according to paragraphs [0201] to [0209], R8 is selected from the group consisting of H, halo and C1-C6 alkyl, wherein Q-Ce alkyl is optionally substituted with OH orNR'V5, where Ri4 and R15 are independently H or C|-C6 alkyl, or R14 and R15 are taken together with the nitrogen to which they are attached to form a C5-C9 heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted.
[0211] In a preferred embodiment of the compounds according to paragraphs [0201] to [0210]. R7 is selected from the group consisting of H, halogen, CrC6 alkyl, -CONR9R!0, -SO2NH2, -SO2NR9Ri0, -Y-heterocycle -Y-heteroaryl, -S-aryl, -S-CrC6 alkyl, -SO-CrC6 alkyl and -SO2-C1-C6 alkyl, wherein Ci-C6 alkyl is unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocycle, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0212] In a preferred embodiment of the compounds according to paragraphs [0201] to [0211],R7is-CONR9R!0.
[0213] In a preferred embodiment of the compounds according to paragraph [0212], R9 and R10 are independently selected from the group consisting of H, Q-Cb alkyl, -Y-O-R11, -
45

WO 2006/010264 PCT/CA2005/001177
Y-(heterocycle), -Y!*CO2-Rn and -Y-(aryl), wherein Ci-C6 alkyl is unsubstituted or is
substituted with one or two of hydroxy or halogen, and the heterocycle, and aryl are
unsubstituted or are substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0214] In a preferred embodiment of the compounds according to paragraph [0212], R9
and R10 are taken together with the nitrogen to which they are attached to form a
pyrrolidinyl, piperidinyl, piperazinyi, morpholinyl, or thiomorpholinyl ring, wherein said
ring is unsubstituted or is substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0215] In a preferred embodiment of the compounds according to paragraphs [0201 ] to
[0209], R7 is selected from the group consisting of H, halogen, CrC6 alkyl, -SO2NR9R!0, -
C(=O)(heterocyclyl), -Y-(heterocyciyl), -Y-(heteroaryl), -S-aryl, -S-C,-C6 alkyl, -SO-Cf-C6
alkyl and -SO2-C|-C6 alkyl, wherein C1-C6 alkyl is unsubstituted or is substituted with one
or two of hydroxy or halogen, and the heterocyclyl, and heteroaryl are unsubstituted or are
substituted with one or two of alkoxy, alkyl, or haloalkyl.
[0216] In a preferred embodiment of the compounds according to paragraphs [0201] to
[0215],Zissuifur.
[0217] In a preferred embodiment of the compounds according to paragraph [0200], the
compounds are represented by the formula B-l:

WO 2006/(110264 PCT/CA2005/001177
CO2-Rn, and -Y-O-R11, wherein Ci-C6 alkyl, cycloalkyl, aryl, heterocycle, and
heteroaryl are each optionally substituted, or R9 and R10 taken together with the nitrogen to which they are attached form a Cs-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted; Y is a bond or is -(C(R")(H))t-! wherein t is an integer from 1 to 6; Yiis-CCrtH)),-; Ru at each occurrence is independently H or C1-C6 alkyl, wherein CpC6 alkyl is optionally
substituted; and R12 is selected from the group consisting of H, Ci-Cg alkyl and -Y-(aryl), wherein C\-C$
alkyl and aryl are optionally substituted.
[0218J In a preferred embodiment of the compounds according to paragraph [0217], R1 is hydrogen or halogen.
J0219] In a preferred embodiment of the compounds according to paragraphs [0217] to [0218], R1 is fluorine.
[0220] In a preferred embodiment of the compounds according to paragraphs [0217] to [0219], R12 is unsubslituted C1-C3 alkyl or unsubstituted benzyl.
[0221] In a preferred embodiment of the compounds according to paragraphs [0217] to [0220], R7 is -C(O)NR9R10.
[0222] In a preferred embodiment of the compounds according to paragraphs [0217] to [0220] R7 is selected from the group consisting of

wherein the members of said group are optionally substituted by 1 to 3 independently selected R3g.
47

WO 2006/010264 PCT/CA2005/001177
[0223] In a preferred embodiment of the compounds according to paragraphs [0217] to [0220J R7 is selected from the group consisting of

wherein the members of said group are optionally substituted with 1 to 3 independently
selected R38.
[0224] In the third aspect, the invention provides a composition comprising a compound
according to any one of paragraphs [0040] - [0223] or as depicted in any of the tables and
examples herein together with a pharmaceutically acceptable excipient.
[0225] The fourth aspect of the invention provides a method of inhibiting VEGF
receptor signaling and HGF receptor signaling, the method comprising contacting the
receptor with a compound according to any one of paragraphs [0040] - [0223] or as depicted
in any of the tables herein, or with a composition according to paragraph [0224]. Inhibition
of VEGF and HGF activity can be in a cell or a multicellular organism. If in a multicellular
organism, the method according to this aspect of the invention comprises administering to
the organism a compound according to any one of paragraphs [0040] - [0223] or as depicted
in any of the tables herein, or a composition according to paragraph [0224]. Preferably the
organism is a mammal, more preferably a human.
[0226] The data presented herein demonstrate the inhibitor}' effects of the VEGF and
HGF inhibitors of the invention. These data lead one to reasonably expect that the
compounds of the invention are useful not only for inhibition of VEGF receptor signaling
and HGF receptor signaling, but also as therapeutic agents for the treatment of proliferative
diseases, including cancer and tumor growth.
[0227] Preferred compounds according to the invention include those described in the
examples below. Compounds were named using Chemdraw Ultra version 6.0.2 or version
48

WO 2006/010264 PCT/CA2005/00I177
8.0.3, which are available through Cambridgesoft.com, 100 Cambridge Park Drive, Cambridge, MA 02140, Namepro version 5.09, which is available from ACD labs, 90 Adelaide Street West, Toronto, Ontario, M5H, 3V9. Canada, or were derived therefrom.
Synthetic Schemes and Experimental Procedures
[0228] The compounds of the invention can be prepared according to the reaction schemes or the examples illustrated below utilizing methods known to one of ordinary skill in the art. These schemes serve to exemplify some procedures that can be used to make the compounds of the invention. One skilled in the art will recognize that other general synthetic procedures may be used. The compounds of the invention can be prepared from starting components that are commercially available. Any kind of substitutions can be made to the starting components to obtain the compounds of the invention according to procedures that are well known to those skilled in the art. I. Synthesis (general schemes)
[0229] Thieno[3,2-b]pyridine based compounds of formula A-Q may be prepared according to the procedures illustrated in the scheme A. Thus, thieno[3,2-b]pyridine-7-ol (I) upon treatment with POCI3 is converted to the chloride II. Treatment of this material with a strong base such as rc-BuLi followed by an addition of carbon dioxide affords the carboxylate HI which is used without purification in the next step, providing the acyi chloride IV (presumably as a hydrochloride salt) upon its reaction with oxalyl chloride. The acyl chloride IV is used for the next step without further purification as well: upon its reaction with different primary and secondary amines the compound IV is converted to a variety of primary and secondary amides V which can further be derivatized via a substitution of the chlorine atom in the pyridine ring.
[0230] Thus, V reacting with substituted 4-nitrophenols in a high boiling point solvent, such as diphenyl ether in the presence of a base such as potassium carbonate, produced the nitro derivatives VI which then are reduced to the amines VII upon treatment with a mixture NiCk/NaBKt (or other conventional reagents). The amines VII also may be used for the next step without further purification, and upon treatment with 2-phenylacetyl isothiocyanates afford phenylacetylthioureas VIII bearing the amido-substituents such as the ones shown in the scheme A.
49

WO 2006/010264 PCT/CA2005/001177

[0231] Substituenrs X and Y (up to three, same or different in each of the indicated benzene rings)are independently selected from halo, Ci-Q alkyl, Q-C6 alkoxy, cyano, nitro, hydroxy, amino, Ci-Q aikylamino
[0232] Tliienof3,2-d]pyrimidine based compounds of formula A-0 may be prepared according to the procedures illustrated in the scheme B. Thus, thieno[3,2-d]pyrimidins-7-ol (IX) upon treatment with POCI3 is converted to the chloride X. Treatment of this material with a strong base such as lithium tetramethylpiperidide (LiTMP) generated in situ followed by an addition of carbon dioxide affords the carboxylate XI which is used without purification in the next step, providing the acyl chloride XII (presumably as a hydrochloride salt) upon its reaction with oxalyl chloride. The acyl chloride XII reacting with different primary and secondary amines is converted to a variety of primary and secondary amides XIII which can further be derivatized via a substitution of the chlorine atom in the pyrimidine ring.
50

WO 2006/010264 PCT/CA2005/001177
51
[0233] Thus, XIII reacting with substituted 4-nitrophenois in a high boiling point solvent, such as diphenyl ether in the presence of a base such as potassium carbonate, produce the nitro derivatives XIV which are then reduced to the amines XV upon treatment with a mixture NiCyNaBH* (or other conventional reagents). The amines XV upon treatment with 2-phenylacetyI isothiocyanates afford the phenylacetylthioureas XVI bearing the amido-substituents such as the ones shown in the scheme B.

WO 2(106/010264 PCT/CA2005/OO1177
reactions) produces heteroaryl-substituted thienopyridines XVIII which can further be derivatized via a substitution of the chlorine atom in the pyridine ring.

[0236] Substituents X and Y (up to three, same or different in each of the indicated benzene rings) are independently selected from halo, C1-C6 alkyl, CrCs alkoxy, cyano, nitro, hydroxy, amino, Cj-Cg alkylamino
[0237] Thus, XVIII reacting with substituted 4-nitrophenols in a high boiling point solvent, such as diphenyl ether in the presence of a base such as potassium carbonate, produced the nitro derivatives XIX which are then reduced to the amines XX upon treatment with a mixture NiCk/NaBHj (or other conventional reagents). The amines XX could be used for the next step without further purification, and upon treatment with 2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XXI bearing the heteroaryl substituents such as the ones shown in the scheme C. Heteroaryls shown in the scheme B, in turn may bear additional substituents exemplified (but not limited to) alky Is, amines, alkylamino, aminoaikyls, alkoxyalkyls, hydroxyalkyls, alkylsulfonylalkyls, etc.- known in the art as solubilizing functionalities.
52

WO 2006/0102(4 PCT/CA2005/001177

[0238] Sub.stitucnts X and Y (up to three, same or different in each of the indicated benzene rings)are independently selected from haio, Q-Ce alkyl, Cj-Q alkoxy, cyano, nitro. hydroxy, amino, C|-C6 alkylamino
[0239] Pyrrolo[2,3-d]pyrimidine based compounds of formula B-0 may be prepared according to the procedures illustrated in the scheme D. Treatment of the 4-chloro-7i?-pyrro!o[2,3-d]pyrimidine (XXII) with an alkyl halide in the presence of a base such as sodium hydride affoids the alkylated chlorides XXIII, which reacting with substituted 4-nitrophenols in a high boiling point solvent, such as diphenyl ether in the presence of a base such as cesium carbonate, produced the nitro derivatives XXIV reduced to the amines XXV upon hydrogenation (or treatment with conventional reducing agents). The amines XXV reacting with 2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XXVI bearing the alkyl substituents such as the ones shown in the scheme D.
5J

WO 2006/010264 PCT/CA2005/0O1177

[0240] Substituents X and Y (up to three, same or different in each of the indicated benzene rings) are independently selected from halo, Q-Cealkyl, Ci-Cealkoxy, cyano, nitro, hydroxy, amino, Ci-Coaikylamino
[0241] Thieno[3,2-b]pyridine based phenylacetylureas of formula A-0 bearing aryl substituents may be prepared according to the procedures illustrated in the scheme E. Thus vhloride II upon lithiation and subsequent bromination is converted to the bromide XXVII that reacting with substituted 4-nitrophenols produces more elaborated compound XXVIII. This material can be used for Suzuki type (and like) reactions with a variety of aryl boronic acids (or boronates), in particular with the ones functionalized with basic groups, thus providing compounds XXIX. Reduction of XXIX with a mixture NiCb/NaBJLt (or other conventional reagents) affords amines XXX. The latter upon treatment with 2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XXXI bearing aryl substituents such as the ones shown in the scheme E.
Scheme F
54

WO 2006/010264 PCT/CA20O5/001177

[0242] Substituents X and Y (up to three, same or different in each of the indicated benzene rings) are independently selected from halo, Ci-C^aHcyl, Ci-Cgalkoxy, cyano, nitro, hydroxy, amino, Ci-Cgalkyfamino
[0243] Bromides XXVIII also can be used for Suzuki type (and like) reactions with a variety of hydroxy phenyl boronic acids (boronates), to form phenolic compounds XXXII. These phenols reacting with different alcohols (Mitsunobu reaction), in particular functional ized with basic groups, provide compounds XXXIII. Reduction of XXXIII with a mixture NiCk/NaBHU (or other conventional reagents) affords amines XXXIV which upon treatment with 2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XXXV bearing the aryl substituents such as the ones shown in the scheme F. II. Specific examples
Scheme 1
55

WO 2006/010264 PCT/CA2005/001177

Example 1
l-(4-(2-(Dimethylcarbamoyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea (8a) Step 1: 7-Chlorothieno[3,2-i]pyridine (2)
[0244] A stirred suspension of thieno[3,2-bJpyridin-7-oi (1, 5.0 g, 33.1 mmol) in POC13 (15 mL) was heated to 105°C in an oil bath for 4 hrs. The resultant solution was cooled to room temperature and the POCI3 was removed under reduced pressure. The residue was cooled in an ice/water bath and cold water was added. The water was made basic with concentrated NH4OH solution and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate and concentrated to produce an oil which was purified by column chromatography (eluent EtOAc-hexane, 1:4) to afford the title compound as a brown solid (4.5 g, 72% yield). 'H NMR (400 MHz, CDC13) 8 (ppm): 8.60 (d, J= 4.9 Hz, 1H), 7.80 (d, /= 5.5 Hz, 1H), 7.60 (d, J= 5.5 Hz, 1H), 7.30 (d, J= 4.9 Hz, 1H). Steps 2-4: 7-Chloro-N,Ar-diniethylthieno[3,2-&]pyridine-2-carboxamide (5) [0245] To a stirred solution of 2 (3.0 g, 17.8 mmol) in dry THF (60 mL) at -78°C was added n-BuLi (7.8 mL, 19.6 mmol, 2.5 M solution in hexanes) and the resultant suspension was stirred for 15 minutes. Solid carbon dioxide (excess) was added and the mixture was allowed to warm to room temperature over a period of 1 hour. The solvent was removed under reduced pressure and the resultant lithium carboxylate 3 was used without further purification (3.88 g, quantitative).
56

Example 20
l-(4-(2-(l-HydroxyelhyI)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-
phenylacetyl)thiourea (18a)
Step 1. 7-Chlorothieno[3,2-b]pyridine-2-carbaldehyde(14)
[0258] To a solution of 2 (200 mg, 1.18 mmol) in dry THF (10 mL) at -78°C was added
n-BuLi (0.57 mL, 1.42 mmol, 2.5 M solution in hexanes) and the resultant suspension was
stirred for 20 min. Dry DMF (0.5 mL, excess) was added and the reaction mixture was
stirred for an additional 2 hrs. The reaction mixture was quenched with methanol at -7S°C
and water was added. The mixture was extracted with EtOAc and the organic extracts were
combined, dried over anhydrous sodium sulfate and filtered. The solvent was removed
under reduced pressure and the resultant yellow solid was triturated with hexane to afford
64

Example 22
l-(4-(6-(2-Morpholincethylcarbamoyl)thieno[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea (26a) Step 1: 4-Chlorothieno[3,2-d]pyrimidine (20)
[0264] To a stirred solution of (COC1)2 (7.33 mL, 84.11 mmol) in anhydrous (CH2Cl)2 (20 mL) at 0°C under nitrogen was added DMF (4.47 mL, 57.18 mmol). After 20 min a solution of thieno[3,2-d]pyrimidin-4(3H)-one (19) (4 g, 26.28 mmol) in anhydrous (CH2Cl)2 (5 mL) was added drop wise to the reaction mixture which was stirred for 20 min at 0°C, wanned to room temperature over another 20 min, heated at 80°C for 1.5 hours, and cooled to room temperature. Finally, the reaction mixture was poured into water and extracted with DCM. The extract was washed sequentially with water, brine, dried over Na2SO4, filtered and evaporated to afford the title compound 20 (4.36 g, 97% yield) as a
67

WO 2006/010264 PCT/CA2005/O01177
Example 29
l-(4-(5-Ethyl-5//-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-
phenylacetyl)thiourea (31b)
[0276] Title compound 31b was obtained according to the scheme 5 using procedures
similar to the ones described for example 28 but using ethyl iodide (instead of methyl
iodide) in the step 1. Characterization of 31b is provided in table 4.
Example 30
l-(4-(5-Benzyl-5//-pynolo[3,2-d]pyrimidin-4-yIoxy)-3-fluorophenyl)-3-(2-
phenylacetyl)thiourea (31c)
[0277] Title compound 31c was obtained according to the scheme 5 using procedures
similar to the ones described for the example 28 but using benzyl bromide (instead of
73
methyl iodide) in the step 1. Characterization of 31c is provided in table 4.

WO 2006/010264 PCT/CA2005/001177

Example 31
l
acetyl)thiourea (36a)
[C278] Title compound 36a (scheme 6) was obtained according to the procedures
similar to the ones described for the example 28 (scheme 5) but using as a starting material
4-chloro-7if-pyrfolo[2,3-rf)pyrimidine 32 (instead of chloride 27). Characterization of 36a
is provided in table 5.
Example 32
l-(4-(7-Ethyl-7ff-pyrrolo[2,3-
acetyl)thiourea (36b)
[0279] Title compound 36b was obtained according to the scheme 6 using the
procedures similar to the ones described for the example 31 but using ethyl iodide (instead
of methyl iodide) in the step 1. Characterization of 36b is provided in table 5.
Example 33
l-(4-(7-Benzyl-7if-pynolo[2>3-f/lpyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenyl
acetyi)thiourea (36c)
[0230] Title compound 36c was obtained according to the scheme 6 using the
procedures similar to the ones described for the example 31 but using benzyl bromide
(instead of methyl iodide) in the step 1. Characterization of 36c is provided in table 5.
74

[0311] To a solution of compound 64 (997 mg, 4 mmol) in CH2Cl2 (12 mL), di-tert-butylcarbonate (1.8 g, 8 mmol) was added and the reaction mixture was stirred for 3 hrs (scheme 14). DMAP (cat.) was added to the solution and the reaction mixture was allowed to stir for additional 76 hours. Solvent was removed under reduced pressure and the crude product was purified by column chromatography, eluent EtOAc/hexane (1:10) to afford the title compound 65 (778 mg, 56% yield) as a colorless oil. MS (m/z): 368.1 / 370.1 (M+Na).
Table 8 Aryl bromides 66-70 prepared according to the scheme 14

93

WO 2006/010264 PC T/CA2UO5/OIM177
94
[0312] To a solution of tert-butyl 2-tert-butyloxycarbonylaminoethyl(methyl)carbamate (600 mg, 2.2 mmol) in dry THF (5 tnL) at 0°C, was added NaH (91 mg, 3.8 mmol) and the reaction was stired for 30 minutes. 3- Bromobenzylbromide was added and the reaction was refluxed for 3 hours, cooled to room temperature and poured into MeOH. Solvents were removed under reduced pressure and the product was partitioned between EtOAc and water. Organic phase was collected and dried over anhydrous sodium sulphate, filtered and evaporated. The crude product was purified by column chromatography on silica gel, eluent EtOAc/hexane (1:5), to afford the title compound 71 (672 mg, 80% yield) as a colourless oil. MS (m/z): 343.0/345.0 (M-Boc).

Example 67
7-[2-Fluoro-4-(3-phen}'iacctyI-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-sulfonicacid methoxy-methyl-amide (85)
Step 1. 7-Chloro-N-methoxy-N-methylthieno[3,2-b]pyridine-2-sulfonamide (82) [0324] To a solution of chloride 2 (scheme 1) (700 mg, 4.14 mmol) in THF (20 ml) was added n-BuLi (2 ml, 4.97 mmol, 2.5 M solution in hexanes) at -78° C and the reaction mixture was stirred for 20 mins. SOa-gas was passed over the surface of the solution for 3 hrs at the same temperature, then for an additional hr at 0°C. The reaction mixture was evaporated. DCM (20 ml) and NCS (605 mg, 4.55 mmol) were added and the reaction mixture was stirred at room temperature for 1.5 hrs, filtered through a celite pad and concentrated to produce a pink solid. The solid was dissolved in acetone (20 ml); MeNH(OMe) hydrochloride (608 mg, 6.21 mmol) and triethylamine (627 mg, 6.21 mmol) were added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The EtOAc solution was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (eluent EtOAc:hexane,
101

Example 87
Ar-(4-(2-(iV,iV-Diethyicarbamimidoyl)thieno[3,2-b]pyridin-7-yloxy)-3-
fluorophenylcarbamothioyl)-2-phenylacetamide(130)
Step 1.7-Chlorothieno[3,2-b]pyridine-2-carbaldehyde oxime (125)
[0366] To a solution of aldehyde 14 (scheme 3) in MeOH was added NH2OH x HCl
(227 mg, 3.26 mmol) in water (0.5 mL) and the mixture was stirred at room temperature for
0.5 h. The solvents were removed by under reduced pressure and the residue was partitioned
between EtOAc and water. The organic phase was dried over anhydrous sodium sulfate,
filtered and evaporated to dryness to afford the title compound 125 (458 mg, 85% yield) as
a white solid. MS (m/z) 213.1/215.1 (M+H).
Step 2.7-Chlorothieno[3,2-b]pyridine-2-carbonitrile (126)
[0367] A solution of the oxime 125 (100 mg, 0.47 mmol) in acetic anhydride (2 ml) was
set to reflux for 3 h and then at 90°C for 48h. The acetic anhydride was removed under
reduced pressure and the residue was partitioned between a cold aqueous K2CO3 solution
and EtOAc. The organic phase was dried over anhydrous sodium sulfate, concentrated to
dryness and remained solid was purified by column chromatography, eluents 25%
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WO 2006/010264 PCT/CA2005/001177
[0385] Following the procedure described above for the synthesis of compound 136a (Table 12, Example 93) but replacing compound 135d with compound 142, title compound , 143 was obtained in 42% yield. Characterization of 143 is provided in the Table 13. Examples 101 and 102
N-(3-Chloro-4-(2-(pyrrolidine-l-carbonyI)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide hydrochloride (144) and N-(3-Methyl-4-(2-(pyrrolidine-l-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide hydrochloride (145) [0386] Compounds 144-145 (examples 101-102) were obtained following the procedures described above for the synthesis of compound 143 (example 100). Characterization of compounds 144-145 is provided in the Table 13. Examples 103 and 104
2-Phenyl-N-(4-(2-(pyrrolidine-l-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide (146) and
N-(3-(Dimethylamino)-4-(2-(pyrrolidine-l-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide (147)
131
[0387] Compounds 146-147 (Examples 103-104) were obtained following the procedures described above for the synthesis of compound 142 (Example 99). Characterization of compounds 145-147 is provided in the Table 13.

Example 150
2-(2,6-Dichlorophenyl)-iV-(3-fluoro-4-(thieno[3J2-b]pyridin-7-
y loxy)pheny lcarbamothioyl)acetamide (192a)
[0438] Starting from the amine 169 (scheme 33), following the procedures described
above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl
isothiocyanate with 2-(2,6-dichIorophenyl)acetyl isothiocyanate, title compound 192a was
obtained in 7 % yield. Characterization of 192a is provided in table 18.
Example 151
iV-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(thiophen-2-
yl)acetamide(192b)
[0439] Starting from the amine 169 (scheme 33), following the procedures described
above for the synthesis of compound 170a (example 133) but replacing 2-pheny!acetyl
isothiocyanate with 2-(thiophen-2-yl)acetyl isothiocyanate, title compound 192b was
obtained in 9 % yield. Characterization of 192b is provided in table 18.
Example 152
2-(2,6-Difluorophenyl)-A'-(3-fluoro-4-(thieno[3)2-b]pyridin-7-
yloxy)phenylcarbamothioyl)acetamide(192c)
[0440] Starting from the amine 169 (scheme 33), following the procedures described
above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl
isothiocyanate with 2-(2,6-difluorophenyl)acetyl isothiocyanate, title compound 192c was
obtained in 23 % yield. Characterization of 192c is provided in table 18.
Example 153
A?-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyI)-l-
phenylcyclopropanecarboxamide (192d)
160

WO 2006/010264 PCT/CA2005/001177
[0441] Starting from the amine 169 (scheme 33), following the procedures described
above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl
isothiocyanate with 1-phenylcyclopropanecarbonyl isothiocyanate, title compound 192d
was obtained in 41 % yield. Characterization of 192d is provided in table 18.
Example 154
JV^-{3-FJuoro-4-(thieno[352-b]pyridin-7-yloxy)phenylcarbamothioy0-2-phenylpropanarnide
(192e)
[0442] Starting from the amine 169 (scheme 33), following the procedures described
above for the synthesis of compound 170a (example 133) but replacing 2-phenyiacetyl
isothiocyanate with 3-methyl-2-phenylbutanoyl isothiocyanate, title compound 192e was
obtained in 49 % yield. Characterization of 192e is provided in table 18.
Example 155
Ar-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-3-phenylpropanamide
(192f)
[0443] Starting from the amine 169 (scheme 33), following the procedures described
above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl
isothiocyanate with 3-phenylpropanoyl isothiocyanate, title compound 192f was obtained in
59 % yield. Characterization of 192f is provided in tabie 18.

WO 2006/010264 PCT/CA2005/001177
164
[0447] Compounds 195b-q (examples 157-181) were obtained starting from the amine 194, following the procedure described above for the synthesis of compound 195a and replacing 2-(2,6-difluorophenyl)acetyl isothiocyanate with an appropriately substituted homologue. Characterization of 195b-q is provided in the table 19.

165

166

167

^xampleT82
i\T-(3-FIuoro-4-(2-(pyrrolidine-l -carbonyl)thieno[3,2-fa]pyridin-7-
yloxy)phenylcarbamothioyl)-2-(2-hydroxyphenyl)acetamide hydrochloride (196a)
[0448] Starting from the compound 195o and following the procedure described above
for the synthesis of compound 155k (scheme 29, example 119), title compound 196a was
obtained in 62% yield. Characterization of 196a is provided in table 20.
Example 183
2-(2,5-Dihydroxyphenyi)-jV-(3-fiuoro-4-(2-(pyrrolidine-l-carbonyi)thieno[3J2-b]pyriuin-7-
yioxy)phenylearbamothioyi)acetaniids hydrochloride (196b)
[0449] Starting from the compound 195p and following the procedure described above
for the synthesis of 196a, title compound 196b was obtained in 83% yield. Characterization
of 196b is provided in table 20.
Example 184
2-(3,4-Dihydroxyphenyl)-i^-(3-fluoro-4-(2-(pyrrolidine-l-carbonyl)thieno[3>2-b]pyridin-7-
yloxy)pheny lcarbamothioy l)acetamide (196c)
[0450] Starting from the compound 195q and following the procedure described above
for the synthesis of 196a, title compound 196c was obtained in 25% yield. Characterization
of 196c is provided in table 20.
168

169

Example 185
A^(4-(2-(4-Hydroxyphenyl)thieno[3,2-6]pyridin-7-yloxy)phenylcarbamothioyI)-2-
phenylacetamide (200)
Step 1.2-Bromo-7-(4-mtrophenoxy)thieno[3.2~b]pyridine (197)
[0451] Starting from the compound 41 (scheme 8) and following the procedure
described above for the synthesis of compound 42 (scheme 8) but replacing 2-fluoro-4-
nitrophenol for 4-nitrophenol, title compound 197 was obtained in 48% yield. LRMS (M+l)
350.9 (100%). 352.9 (100%).
Step 2.4-(7-(4-Nitrophenoxy)thieno[3,2-Z>]pyridin-2-yl)phenol (198)
[0452} Starting from the compound 197 and following the procedure described above
for the synthesis of compound 153 (scheme 28), title compound 198 was obtained in 81%
yield. LRMS (M+l) 365.0 (100%).
Step 3.4-(7-(4-Aminophenoxy)mieno[3>%yridin-2-yl)phenol (199)
[0453J Starting from the compound 198 and following the procedure described above
for the synthesis of compound 154 (scheme 28), title compound 199 was obtained in 83%
yield. LRMS (M+l) 335.0 (100%).
170

Example 208
l-(4-(2-(Methylsulfonyl)thieno[3,2-b]pyridin-7-y]oxy)-3-fluorophenyl)-3-(2-phenylaceiyi)thiourea (238)
Step 1: 7-(2-Fluoro-4-nitrophenoxy)-2-(methylsulfonyl)thieno[3,2-b]pyridine (236) £0503] To a solution of 233 (50 mg, 0.142mmol) in DCM (2mL), was added mCPBA (77%, 33 mg, 0.142 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour, water was added and the phases were separated. The organic layer was collected, washed with a 1% sodium hydroxide solution, dried over anhydrous Na2SC>4 and concentrated under reduced pressure to afford title compound 236 (46 mg, 88% yield, crude) as a yellow solid which was used in the next step without additional purification. MS (m/z): 369.0 (M+l). Step 2:4-(2-(Methylsulfonyl)thieno[3,2-b]pyridin-7-yloxy)-3-iluorobenzenamine (237) [0504] To a solution of 236 (45 mg, 0.122 mmol) in acetic acid (4 mL) at 100"C, was added iron powder (34 mg, 0.611 mmol). The reaction mixture was stirred for 5 minutes, filtered through a celite pad and concentrated under reduced pressure to afford title compound 237 (20 mg, 48% yield, crude) as a yellow oil that was used in the next step without further purification. MS (m/z): 339.0 (M+l).
Step 3. l-(4-(2-(MethylsuIfonyl)thieno[3,2-b]pyridin-7-yloxy>-3-fluorophenyl)-3-(2-phenylacetyl)thiourea (238)
189

WO 2006/010264 PCT/CA2005/OO1177
Step 2:4-(2-(4-Methyl-l^-pyrazol-l-yl)thieno[3,2-&]pyridin-7-yloxy)benzenaraine (257)
[0525] To a solution of 256 (168.4 mg, 0.478 mmol) and NiCl2 x 6H2O (226 mg, 0.956
mmol) in MeOH/THF (10/10 mL) NaBH, (72 mg, 1.92 mmol) was carefully added. The
reaction mixture was stirred for 10 min, concentrated to dryness and the resultant solid was
suspended in 10% HC1. The aqueous solution was basifiied (pH -11) with concentrated
aqueous NH4OH and extracted with EtOAc. The organic extract was collected, dried, over
anhydrous NajSC^ and concentrated under reduced pressure, to afford title compound 257
(134.6.mg3 87% yield) as a white solid. MS (m/z): 322.09 (M+l).
Step3:Ar-(4-(2-(4-Methyl-ii/-pyrazol-I-yl)thieno[3)2-i]pyridin-7-
yloxy)phenylcarbamothioyl)-2-phenylacetamide(258a)
[0526] To a suspension of the 257 (134.6 mg, 0.418 mmol) in THF (4.2 mL) was added
2-phenylacetyl isothiocyanate (111 mg, 0.627 mmol). The reaction mixture was stirred for 1
hr at room temperature, transferred onto a chromatography column and eluted wit a gradient
of gradient EtOAc/hexane, 1:1 to 2:1, to provide a beige solid which was triturated with
diethyl ether to afford title compound 258a (31 mg, 15% yield) as a white solid.
Characterization of 258a is provided in the table 23.
Example 216
JVK4-(2-(lH-Pyrazol-l-yl)thieno[3,2-fe]pyridin-7-yloxy)phenylcarbarnothioyl)-2-
phenylacetamide (258b)
[0527] Following the procedures described above for the synthesis of compound 258a
(example 235, scheme 58) but replacing 4-methy]-l#-pyrazole in the step 1 with IH~
pyrazole, title compound 258b was obtained. Characterization of 258b is provided in the
table 23.
Example 217
iVr-(4-(2-(3,5-Dimethyl-li?-pyrazol-l-yl)thieno[3,2-6]pyridin-7-
yloxy)pheny lcarbamothioyl)-2 -phenylacetami de (25 8c)
[0528] Following the procedures described above for the synthesis of compound 258a
(example 215, scheme 58) but replacing 4-methyl-lif-pyrazole in the step I with 3,5-
dimethyl-I/f-pyrazoie, title compound 258c was obtained. Characterization of 258c is
provided in the table 23.
198

Example 223
N-(4-(6-Bromothieno[3r2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-
phenylacetamide (274)
Step 1. 6-Bromothieno[3,2-b]pyridin-7-ol (270)
[0543] To a solution of thieno[3,2-b]pyridin-7-ol (1,2.55g, 16.87 mmol) in acetic acid.
(50mL) was added bromine(1.7 mL, 32.72 mmol). The mixture was heated at 110°C for 1h,
cooled and the resultant precipitate was separated by filtration, to afford the title compound
270 (4.47g, crude) as a dark brown powder, which was used in next step without further
purification. M/S (m/z): 231.9(M+H) (found).
Step 2.6-Bromo-7-chlorothieno[3,2-b]pyridine (271)
[0544] DMF (0.72mL) was added slowly to a solution of (COC1)2 in DCE at 0°C and
the mixture was stirred for 30 min, followed by addition of 270 (crude from above). The
combined mixture was stirred for 10 min at the same conditions and was heated to reflux for
3h. After cooling the mixture was concentrated and partitioned between DCM and water.
Organic phase was collected and dried over anhydrous Na2SO4, filtered and concentrated.
The residue was purified by flash column chromatography (eluent EtOAc), to afford the
title compound 271 (0.66g, 70% yield based on compound 1) as a yellowish solid. MS
(m/z): 249.0(M+H) (found).
Step 3.6-Bromo-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (272)
[0545] Starting from the compound 271 and following the procedure described above
for the synthesis of compound 260 (scheme 59, example 218, step 2), title compound 272
was obtained in 61% yield as an off-white solid. MS (m/z): 368.9(M+H).
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WO 2006/010264 PCT/CA2005/001177
In Vitro Receptor Tyrosine Kinase Assays (c-Met/HGF receptor and VEGF receptor KDR)
[0597] These tests measure the ability of compounds to inhibit the enzymatic activity of recombinant human c-Met/HGF receptor and VEGF receptor enzymatic activity. [0598] A 1.3-kb cDNA corresponding to the intracellular domain of c-Met or c-Met IC (Genbank accession number NP000236-1 amino acid 1078 to 1337) was cloned into the BamHI/XhoI sites of the pBlueBacHis2A vector (Invitrogen) for the production of a histidine-tagged version of that enzyme. This constuct was used to generate recombinant baculovirus using the Bac-N-Blue™ system according to the manucfacturer's instructions "(Invitrogen)
[0599] The c-Met IC protein was expressed in Hi-5 cells (Trichoplnsia Ni) upon infection with recombinant baculovirus construct. Briefly, Hi-5 cells grown in suspension and maintained m serum-free medium (SfflOO II supplemented with gentamycin) at a cell density of about 2 X 106 cells/ml were infected with the abovementioned viruses at a multiplicity of infection (MOI) of 0.2 during 72 hours at 27°C with agitation at 120 rpm on a rotary shaker. Infected cells were harvested by centrifugation at 398g for 15 min. Cell pellets were frozen at -S0°C until purification was performed.
[0600] All steps described in cell extraction and purification were performed at 4°C. Frozen Hi-5 cell pellets infected with the C-Met IC recombinant baculovirus were thawed and gently resuspended in Buffer A (20mM Tris pH 8.0,10% giycerol, lug/ml pepstatin, 2ug/ml Aprotinin and leupeptin, 50µg/ml PMSF, 50µg/mi TLCK and 10µM E64, 0.5mM DTT and lmM Levamisole) using 3 ml of buffer per gram of cells. The suspension was Dounce homogenized after which it was centrifuged at 22500g, 30 min., 4°C. The supernatant (cell extract) was used as starting material for purification of c-Met IC. [0601] The supernatant was loaded onto a QsepharoseFF column (Amersham Biosciences) equilibrated with Buffer B (20mM Tris pH 8.0,10% glycerol) supplemented with 0.05M NaCL Following a ten column volume (CV) wash with equilibration buffer, bound proteins were eluted with a 5 CV salt linear gradient spanning from 0.05 to 1M NaCl in Buffer B. Typically, the conductivity of selected fractions ranked between 6.5 and 37 mS/cm. This Qsepharose eluate had an estimated NaCl concentration of 0.33M and was supplemented with a 5M NaCl solution in order to increase NaCl concentration at 0.5M and also with a 5M Imidazole (pH 8.0) solution to achieve a final imidazole concentration of 15mM. This material was loaded onto a HisTrap affinity column (GE Healthcare) equilibrated with Buffer C (50mM NaPO4 pH 8.0, 0.5M NaCl, 10% glycerol) supplemented
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with 15mM imidazole. After a 10 CV wash with equilibration buffer and an 8 CV wash with buffer C + 40mM imidazole, bound proteins were eluted with an 8 CV linear gradient (15 to 500mM) of imidazole in buffer C. C-Met IC enriched fractions from this chromatography step were pooled based on SDS-PAGE analysis. This pool of enzyme underwent buffer exchange using PD-10 column (GE Healthcare) against buffer D (25mM HEPES pH 7.5, 0.1M NaCL 10% glycerol and 2mM D-mercaptoethanol) Final C-Met IC protein preparations concentrations were about 0.5 mg/ml with purity approximating 80%. Purified c-Met IC protein stocks were supplemented with BSA at 1 mg/ml, aliquoted and frozen at -80°C prior to use in enzymatic assay.
[0602] In the case of VEGF receptor KDR aT.6-leb cDNA corresponding to the catalytic domain of VEGFR2 or KDR (Genbank accession number AF035121 amino acid 806 to 1356) was cloned into the Pst 1 site of the pDEST20 Gateway vector (Invitrogen) for the production of a GST-tagged version of that enzyme. This constuct was used to generate recombinant baculovirus using the Bac-to-Bac™ system according to the manucfacturer's instructions (Invitrogen)
[0603] The GST-VEGFR2806-1356 protein was expressed in Sf9 cells (Spodaptera frugiperda) upon infection with recombinant baculovirus construct. Briefly, Sf5 ceiis grown in suspension and maintained in serum-free medium (Sf900 II supplemented with gentamycin) at a cell density of about 2 X 106 cells/ml were infected with the abovementioned viruses at a multiplicity of infection (MOI) of 0.1 during 72 hours at 27°C with agitation at 120 rpm on a rotary shaker. Infected cells were harvested by centrifitgation at 39Sg for 15 min. Cell pellets were frozen at -80°C until purification was performed. [0604] All steps described in cell extraction and purification were performed at 4°C. Frozen Sf9 cell pellets infected with the GST-VEGFR2806-1356 recombinant baculovirus were thawed and gently resuspended in Buffer A (PBS pH 7.3 supplemented with lµg/ml pepstatin, 2µg/ml Aprotinin and Ieupeptin, 50µg/ml PMSF, 50µg/ml TLCK and 10µM E64 and 0.5mM DTT) using 3 ml of buffer per gram of cells. Suspension was Dounce homogenized and 1% Triton X-100 was added to the homogenate after which it was centrifuged at 22500g, 30 min., 4°C. The supernatant (cell extract) was used as starting material for purification of GST-VEGFR2806-1356-
[0605] The supernatant was loaded onto a GST-agarose column (Sigma) equilibrated with PBS pH 7.3. Following a four column volume (CV) wash with PBS pH 7.3 + 1% Triton X-100 and 4 CV wash with buffer B (50mM Tris pH 8.0,20% glycerol and 100mM NaCl), bound proteins were step eluted with 5 CV of buffer B supplemented with 5mM
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DTT and 15mM glutathion.GST-VEGFR2806-1356 enriched fractions from this chromatography step were pooled based on U.V. trace i.e. fractions with high O.D.280- Final GST-VEGFR2806-1356 protein preparations concentrations were about 9.7 mg/ml with purity-approximating 70%. Purified GST-VEGFR2806-1356 protein stocks were aliquoted and frozen at -80°C prior to use in enzymatic assay.
[0606] Inhibition of c-Met/HGF receptor and VEGFR/KDR. was measured in a DELF1A™ assay (Perkin Elmer). The substrate poly(Glu4,Tyr) was immobilized onto black high-binding polystyrene 96-well plates. The coated plates were washed and stored at 4 °C. During the assay, enzymes were pre-incubated with inhibitor and Mg-ATP on ice in polypropylene 96-well platesTor 4 minutes, and then transferred to the coated plates. The subsequent kinase reaction took place at 30 °C for 10-30 minutes. ATP concentrations in the assay were 10 uM for C-Met (5X the Km) and 0.6 uM for VEGFR/KDR (2X the Km). Enzyme concentration was 25 nM (C-Met) or 5 nM (VEGFR/KDR). After incubation, the kinase reactions were quenched with EDTA and the platen were washed. Phosphorylated product was detected by incubation with Europium-iabeled anti-phosphotyrosine MoAb. After washing the plates, bound MoAb was detected by time-resolved fluorescence in a Gemini SpectraMax reader (Molecular Devices). Compounds were evaluated over a range of concentrations and ICso's (concentration of compounds giving 50% inhibition of enzymacic activity) were determined. C-Met phosphoryiatioR eell-basetl assay
[0607] This test measures the ability of compounds to inhibit HGF stimulated auto-phosphorylation of the c-Met/HGF receptor itself in a whole cell system. [0608] MNNGHOS cell line expressing TPR-MET fusion protein were purchased from ATCC. The TPR-MET is the product of a chromosomal translocation placing the TPR locus on chromosome 1 upstream of the MET gene on chromosome 7 encoding for it's cyioplasmic region catalytic domain. Dimerization of the Mr 65,000 TPR-Met oncoprotein through a leucine zipper motif encoded by the TPR portion leads to constitutive activation of the met kinase. Constitutive autophosphorylation occurs on residues Tyr361/365/366 of TPR-Met. These residues are homologous to Tyrl230/1234/]235 of MET which become phosphorylated upon dimerization of the receptor upon HGF binding. [0609] Inhibitor of c-Met formulated as 30 mM stocks in DMSO. For MNNGHOS treatments, cells, compounds were added to tissue culture media at indicated doses for 3 hours prior to cell lysis. Cells were lysed in ice-cold lysis buffer containing 50 mM HEPES (pH 7.5), 150 mM NaCl, 1.5 mM MgC12,10 % glycerol, 1 %Triton X-100, 1 mM 4-(2-
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Aminoethyl)benzenesulfonyl fluoride hydrochloride, 200 µM sodium orthovanadate, 1 mM sodium fluoride, 10 µg/ml of leupeptin, 10 µg/ml of aprotinin/ml, 1 µg/ml of pepstatin and 50ug/ml Na-p-Tosyl-L-lysine chloromethyl ketone hydrochloride . [0610] Lysate were separated on 5-20% PAGE-SDS and immunoblots were performed using Immobilon P polyvinylidene difluoride membranes (Amersham) according to the manufacturer's instructions for handling. The blots were washed in Tris-buffered saline with 0.1% Tween 20 detergent (TBST). Tyr361/365/366 of TPR-Met were detected with polyclonal rabbit antibodies against tyrosine phosphorylated Met (Biosource International) and secondary antibodies anti-rabbit -horseradish peroxidase (Sigma) by chemiluminescenee assays (Amersham, ECL) were performed according to theT manufacturer's instructions and followed by film exposure. Signal was quantitated by densitometry on Alpha-Imager. IC50 values were defined as the dose required to obtain 50% inhibition of the maximal HGF stimulated phosphorylated c-Met levels.
In Vivo Solid Tamor Disease Model
[0611] This test measures the capacity of compounds to inhibit solid tumor growth. [06121 Tumor xenografts were established in the flank of female athymic CD1 mice (Charles River Inc.). by subcutaneous injection of 1X106U87, A431 or SKLMS cells/mouse. Once established, tumors were then serially passaged s.c. in nude mice hosts. Tumor fragments from these host animals were used in subsequent compound evaluation experiments. For compound evaluation experiments female nude mice weighing approximately 20g were implanted s.c. by surgical implantation with tumor fragments of ~30 mg from donor tumors. When the tumors were approximately 100 mm3 in size (~7-10 days following implantation), the animals were randomized a separated into treatment and control groups. Each group contained 6-S tumor-bearing mice, each of which was ear-tagged and followed individually throughout the experiment
[0613] Mice were weighed and tumor measurements are taken by calipers three times weekly, starting on Day 1. These tumor measurements were converted to tumor volume by the well-known formula (L+W/4)3 4/3#. The experiment was terminated when the control tumors reached a size of approximately 1500 mm3. In this model, the change in mean tumor volume for a compound treated group / the change in mean tumor volume of the control group (non-treated or vehicle treated) x 100 (##T / ##C) was subtracted from 100 to give the percent tumor growth inhibition (%TGI) for each test compound. In addition to tumor volumes, body weight of animals were monitored twice weekly for up to 3 weeks.
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[0614] The activities of a number of compounds according to the invention measured by various assays are displayed in the following table, Table 24. In the table, "a" indicates inhibitory activity at a concentration of less than 50 nanomolar; "b" indicates inhibitory activity at a concentration > 50 but 500 nanomolar; and "e" indicates no activity as measured by that assay.

WO 2006/010264 PCT/CA2005/001177
[0615] In the following table, Table 25, "a" indicates % TGI in the range of 75-100; "b" indicates % TGI in the range of 50-74; "c" indicates % TGI in the range of 25-49, and "d" indicates % TGI in the range of 0-24. Regiment of administration was once daily.
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WHAT IS CLAIMED IS:
1. A compound of the formula (A), that are inhibitors of VEGF receptor signaling and HGF receptor signaling:

and pharmaceutically acceptable salts and complexes thereof, wherein
T is selected from the group consisting of arylalkyl, cycloalkyl, heterocyclyl, aryl and
heteroaryl, wherein each of said arylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is
optionally substituted with. 1 to 3 independently selected R20;
each R20 is independently selected from the group consisting of -H, halogen, trihalomethyi, -CN, -NO2r -NH2, -OR17, -OCF3, -NR17R18, -S(0)o-2R)7, -S(O)2NRl7R17, -C(O)OR17, -C(O)NR17R17, -N(R17)SO2R17, -N(R17)C(O)R17, -N(R17)C(O)OR17, -C(O)R17, -C(O)SR17, CrC4 alkoxy, C1-C4 alkylthio, -O(CH2)naryl, -O(CH2)nheteroaiyl, -(CH2)0-5(aryl), -(CH2)0.5(heteroaryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2(CH2)0-4-T2, an optionally substituted C1-4 alkylcarbonyl, C1-4 alkoxy, an amino optionally substituted by C1-4 alkyl optionally substituted by C1-4 alkoxy and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMe, -OEt, -NH2, -NHMe, -NMe2, -NHEt and -NEt2, and wherein the aryl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
W is selected from the group consisting of O, S, NH and NMe;
Z is selected from the group consisting of O, or S and NH;
X and X1 are independently selected from the group consisting of H, C1-C6 alkyl, halo, cyano, or nitro, wherein C1-C6 alkyl is optionally substituted, or
X and X' taken together with the atom to which they are attached, form a C3-C7 cycloalkyl;
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R1, R2, R3 and R4 independently represent hydrogen, halo, trihalomethyl, -CN, -NO2, -NH2, -OR17, -NR17R18, -C(O)OR17, -C(O)R17, C1-C4 alkoxy, C1-C4 alkylthio, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl are optionally substituted;
R17 is selected from the group consisting of H and R18;
R18 is selected from the group consisting of a (C1-C6)alkyl, an aryl, a aryI(C1-C6)alkyl, a
heterocyclyl and a heterocyclyl(C1-C6)alkyl, each of which is optionally substituted, or
R17 and R18, taken together with a common nitrogen to which they are attached, form an
optionally1 substituted five- to seven-membered heterocyclyl, the optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from the group consisting of N, O, S and P;
Rl6 is selected from the group consisting of-H, -CN, -(CH2)0-5(aryl), -(CH2)o-5(heteroaryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -CH2(CH2)0-4-T2, an optionally substituted C1-4 alkylcarbonyl and a satoated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMc, -OEt -NH2, -NHMe, -NMe2 -NHEt and -NEt2, and wherein the aryl, heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted;
Q is selected from the group consisting of CH2,0, S, N(H), N(C1-C6 alkyl), N-Y-(aryl)s -N-
OMe, -NCH20Me and -N-Bn;
D is selected from the group consisting of C-E and N;
L is N, or CR, wherein R is selected from the group consisting of-H, halo, -CN, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, wherein C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted: and
E is selected from the group consisting of E1, E2 and E3, wherein
E1 is selected from the group consisting of -H, halogen, nitro, azido, C1-C2 alkyl, C3-C10 cycloalkyl, -C(O)NR42R43, -Y-NR42R43; -NR42C(=O)R43, -SO2R42, -SO2NR42R43, -NR37SO2R42, -NR37SO2NR42R43, -C(=N-OR42)R43, -C(=NR42)R43, -NR37C(=NR42)R435 -C(=NR42)NR37R43, -NR37C(=NR42)NR37R43, -C(O)R42, -CO2R42, -C(O)(heterocyclyl), -C(O)(C6-C10 aryl), -C(O)(heteroaryl).. -Y-(C6-C]0 aryl), -Y-(heteroaryl), -Y-(5-l0 membered heterocyclic), -NR6aR6b, -NR6aSO2R6b, -NR6aC(O)R6b, -OC(O)R6b, -NR6aC(O)OR6b -OC(O)NR6aR6b,-OR6a,. -SR6a, -S(O)R6a, -SO2R6a, -SO3R6a, -SO2NR6aR6b,
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-SO2NR42R43, -COR6a, -CO2R6a, -CONR6aR6b, -(C1-C4)fluoroalkyl, -(C1-C4)fluoroalkoxy, -(CZ3Z4)aCN, wherein n is an integer ranging from 0 to 6, and the aforementioned E1 groups other than -H and halogen are optionally substituted by 1 to 5 independently selected R38, or El is selected from a moiety selected from the group consisting of-(CZ3Z4)a-aryl, -(CZ3Z4)3-heterocycle, (C2-C6)alkynyl, -(CZ3Z4)a-(C3-C6)cycloalkyl, -(CZ3Z4)a-(C5-C6)cycloalkenyl, (C2-C6) alkenyl and (C5-C6)aIkyL which is optionally substituted with 1 to 3 independently selected Y2 groups, where a is 0,1,2, or 3, and wherein when a is 2 or 3, the CZ3Z4 units may be the same or different; wherein each R38 is independently selected from halo, cyano, nitrortrifluoromethoxy,triiluoromethyl, azido, -C(O)R40, -C(0)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -NR36R39, -OR37, -SO2NR36R39, C,-C6 allcyl, -(CH2)jO(CH2)iNR36R39, -(CH2)nO(CH2)iOR37, -(CH2)nOR37, -SCO^C-Ce alkyl), -(CH2)a(C6-C10 aryl), -(CH2)n(C5-Cio heteroaryl), -(CH2)n(5-10 membered heterocyclyl); -C(O)(CH2)n(C6-C]0 aryl), -(CH2)nO(CH2)j(C6-Cio aryl), -(CH2)nO(CH2)i(5-10 membered heterocyclyl), -C(O)(CH2)n(5-10 membered heterocyclyl), -(CH2)jNR39(CH2)iNR36R39.. -(CH2)jNR39CH2C(O)NR36R39s -(CH2)jNR39(CH2)iNR37C(O)R40, -(CH2)jNR39(CH2)nO(CH2)jOR37, -(CH^jNR^Ca^iSCO^CCj-Ce alkyl), -(CH2)jNR39(CH2)nR36, -SO2(CH2)n(C6-CI0 aryl), -SO2(CH2)n(5-I0 membered heterocyclyl), -(CH2)nNR36R39, -NR37SO2NR36R39, SO2R36, C2-C6 alkenyl, C3-C10 cycloalkyl and Q-C6 alkylamino, wherein j is an integer ranging from 0 to 2, n is an integer ranging from 0 to 6, i is an integer ranging from 0 to 6, the -(CH2)i- and -(CH2)n~ moieties of the foregoing R38 groups optionally include a carbon-carbon double or triple bond where n is an integer between 2 and 6, and the alkyl, aryl, heteroaryl and heterocyclyl moieties of the foregoing RjS groups are optionally substituted by one or more substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -OH, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -(CH2)nNR36R39; d-C6 alkyl, C3-Cl0 cycloalkyl, -(CH2)n(C6-Cl0 aryl), -(CH2)n(5-10 membered heterocyclyl), -(CH2)nO(CH2)jOR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6;
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each R42 and R43 is independently selected from the group consisting of H, d-Q alkyl, Ci-C6 heteroalkyl, -Y-(C3-C10 cycloalkyl), ~Y-(C6-Cio aryl), -Y-(C6-Cio heteroaryl), -Y-(5-10 membered heterocyclic), -Y-O-Y'-OR37, -Yi-CO2-R37, and -Y-OR37, wherein the alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic moieties of the foregoing R42 and R43 groups are optionally substituted by 1 or more substituents independently selected from R44, wherein
Y is a bond or is -(C(R37)(H))n,
n is an integer ranging from 1 to 6. and
R42 and R43 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted by 1 to 5 independently selected R44 substituents, with the proviso that R42 and R43 are not both bonded to the nitrogen directly through an oxj'gen;
each R44 is independently selected from the group consisting of halo, cyano, nitro, trifluoromeUioxy, trifluoromethyl, azido, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR3(iC(O)R3S, -C(O)NR36R39, -NR36R39, -OR37, -SO2NR36R39, -SO2R36, -NR36SO2R39, -NR36SO2NR37R4\ d-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C!o cycloalkyl -Ci-C6 alkylamino, -(CH2)jO(CH2)iNR36R39, -(CH2)nO(CH2)iOR37, -(CH2)nOR37, -S(O)j(Ci-Q alkyl), -(CH2)n(C6-Cj0 aryl), -(CH2)n(5-10 membered heterocyclic), -C(O)(CH2)n(C6-C10 aryl), -(CH2)nO(CH2)j(C6-Cio aryl), -(CH2)nO(CH2)i(5 to 10 membered heterocyclic), -C(O)(CH2)n(5 to 10 membered heterocyclic), -(CH^jNR39^^),^^3^39, -(CH2)jNR39CH2C(O)IsfR36R39, -(CH2)fNR39(CH2)iNR37C(O)R40, -(CH2)jNR39(CH2)nO(CH2)iOR37, -(CH^NR^CH^SCOJjCCi-Ce alkyl), -(CH2)jNR39(CH2)nR36, -SO2(CH2)n(C6-C10 aryl), and -SO2(CH2)n(5 to 10 membered heterocyclic) wherein, j is an integer from 0 to 2, n is an integer from 0 to 6 and i is an integer ranging from 2 to 6, the -(CH2)i- and -(CH2)ni-moieties of the foregoing R44 groups optionally include a carbon-carbon double or triple bond wherein n is an integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoing R44 groups are optionally substituted by 1 or more substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -OH, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40,-NR36C(O)R39, -
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eacli Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidirxo, amidino, methylguanidino, azido, -C(O)Z7, -OC(O)NH2, -OC(O) NHZ7, -OC(O)NZ7ZS, -NHC(O)Z7, -NHC(O)NH2, -NHC(O)NHZ7, -NHC(O)NZ7ZS, -C(O)OH, -C(O)OZ7, -C(O)NH2, -C(O)NHZ7,-C(O)NZ7ZS, -P(O)3H2, -P(O)3(Z7)2, -S(O)3H, -S(O)Z7, -S(O)2Z7, -S(O)3Z7, -Z7, -OZ7, -OH, -NH2, -NHZ7, -NZ7Z8., -C(=^NH)NH2J-C(=NOH)>]H2, -N-moipholino, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cj-C6)haloalkyl, (C2-C6)haloalkenyl, (C2-C6)haloalkynyl, (d-C6)haloalkoxy, -(CZ9ZI0)rNH2, -(CZ9ZI0)rNHZ3, -(CZ9Z10)fNZ7Zs, -X6(CZ9ZJ0)r-(C3-
heterocycle, wherein ris 1,2, 3 or 4; X6 is selected from the group consisting of O, S, NH, -0(0)-, -C(0)NH-, -C(O)O-, -S(O)-, -
S(O)2- and -S(O)3-; Z7 and Z8 are independently selected from the group consisting of an alkyl of 1 to 12 carbon
atoms, an alkeny] of 2 to 12 carbon atoms, an aikynyl of 2 to 12 carbon atoms, a
cycioaikyi of 3 to 8 carbon atoms, a cycloalkenyl of 5 to S carbon atoms, an aryl of 6 to
14 carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7 to 15 carbon atoms.
and a heteroaralkyl of 5 to 14 ring atoms, or Z7 and Z8 together may optionally form a heterocycle; Z9 and Z10 are independently selected from the group consisting of H, F, a (Ci-Ci2)alkyl, a (€&-
Ct4)aryl, a (Cj-Cj4)heteroaryl, a (C7-C]5)aralkyl and a (Cs-Ci^heteroaralkyl, or Z9 and Z10 are talcen together form a carbocycle, or
two Z9 groups on adjacent carbon atoms are taken together to form a carbocycle; or any two Y2 or Y3 groups attached to adjacent carbon atoms may be taken together to be -
O[C(Z9)(Z10)]rO or-O[C(Z9)(Z10)jH-b or any two Y2 or Y3 groups attached to the same or adjacent carbon atoms may be selected
together to form a carbocycle or heterocycle; and wherein any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH
(methine) group which is not attached to a halogen, SO or SO2 group or to a N, O or S
atom optionally bears on said group a substituent selected from hydroxy, halogen, (Cr
C)alkyl, (CrC4)alkoxy and an -N[(CrC4)alkyl][(CrC4)alkyl];
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E2 is -C=CH or -C=C-(CR45R45)n-R46;
R45 is independently selected from the group consisting of H, a (Cj-C6)alkyl and a (C3-C8)cycloalkyl;
R46 is selected from the group consisting of heterocyclyl, -N(R47)-C(O>N(R47)(R48), -N(R47)-C(S)-N(R47)(R48), -N(R47>C(O)-OR4\ -N(R47)-C(O)-(CH2)n-R48.. -N(R47)-SO2R47, -(CH2)nNR47R48, -(CH2)nOR48, -(CH2)nSR49, -(CH2)nS(O)R49, -(CH2)nS(O)2R49, -OC(O)R49, -OC(0)OR49, -C(O)NR47R48, heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, - (CrCg)alkyK -GN, ~SO2R50-and -(G^^NR^-'rand aryl optionally-substituted^vith-one- - -or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, (C1-C6)allcyl, -CN, -SO2R50 and -(CH2)nNR50R51;
R47 and R48 are independently selected from the group consisting of H, (Cj-C^alkyl, (C3-
C8)cycloalkyL heterocyclyl, -(CH2)nNR50R51, -(CH2)nOR50, -(CH2)nC(O)R497 -C(O)2R49, -(CH2)nSR49, -(CH2)nS(O)R49, -(CH2)nS(O)2R49, -(CH2)nR49, -(CH2)nCN, aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (CrC6)alkoxy, -NO2; (CrC6)aIkyl, -CN, -(CH2)nOR4y, -(CH2)nheterocyclyl; -(CH2)nlieteroaryl, -SO2R50 and -(CH2)nNRS0R51, and heteroaiyl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Cj-C6)alkoxy, -NO2, (C,-C6)alkyl, -CN, -(CH2)nOR49, -(CH2)nheterocyclyl, -(CH2)nheteroaryl, -SO2R50 and -(CH2)nNR50RM5 or
R47 and R48, together with the atom to which they are attached, form a 3-8 membered ring;
R49 is selected from the group consisting of (Ci-C6)all
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selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy, -NO2, (CrC6)alkyl, -
CN, -SO2R50 and -(CH2)nNR50R5J; R30 and R51 are independently selected from the group consisting of H, (Ci-C6)alkyl, (C3-
C8)cyclcalkyl and -C(O)R45, or
R50 and. R51, together witli the atom to which they are attached, form a 3-8 membered ring; and E3 is ihe group defined by -(Z1;)-(Z12)m-(Z13)mi3 wherein Zn is heterocj'clyl or heterocyclylene;
Zn is selected from the group consisting of OC(O), OC(S) and C(O); Znis_selected-fejm thegroup consisting-ofheterocyclylraralkyl,^(H)R3\(ei-e3)alkyr,-OR52,
halo, S(O)2R50', (CrC3)hydroxyalkyl and (Ci-C3)haloalkyl; rn isOor 1; ml isOor 1; R" is selected from the group consisting of H, '(CH2)!,S(O)2Rsl R55NR53R53, (Ci-C3)alkyl, -
(CH2)qORS3, -C(O)R54 and -C(O)OR53; qisO, 1,2, 3 or 4; R53 is (C)-C3)alkyi; RH is (CrC3)alkyi orN(H)R53; R-sis(Ci-C6)alkyi;and R5t) is selected from die group consisting of NR2, (Ci-C3)alkyl and OR52.
2. The compound according to claim 1, wherein T is aryl or heteroaryl, wherein each of
said aryl and heteroaryl is optionally substituted with 1 to 3 independently selected R20. '•"¦'
3. The compound according to claim 1, wherein T is selected from the group consisting^of
aryiallcyj, cycloalkyl and helerocyclyl, wherein each of said arj'lalk>'l5 cycloalkyl and '¦'"
heterocyclyl is optionally substituted with 1 to 3 independently selected R20.
4. The compound according to claim 1, wherein R20 is selected from the group consisting
of H, halogen, -OR17 and -C(O)OR17.
5. The compound according to claim 1, wherein R20 is fluorine or chloride.
6. The compound according to claim 1, wherein Wis O,
7. The compound according to claim 1, wherein Z is S or O.
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8. The compound according to claim 1, wherein Z is S.
9. The compound according to claim 1, wherein X and X1 are independently selected from
the group consisting of H and Ci-C6alkyl, wherein the CrCialkyl is optionally substituted.
10. The compound according to claim 1, wherein X and X1 are both H.
11. The compound according to claim 1, wherein X and X1 taken together with the atom to
which they are attached, form a Cs-Cycyeloalkyl.
12. The compound according to claim 1, wherein R1, R2, R3 and R4 are independently
selected from the group consisting of H, halogen, trihalomethyl, OR17, -NRI7RIS and Cj-
C6alkyl.
13. The compound according to claim 1, wherein R!3 R2 and R4 are independently selected
from the group consisting of H, halo and -ORL7.
14. The compound according to claim 1, wherein R1 is H or halogen.
15. The compound according to claim 1, wlieisiu R is halogen.
16. The compound according to claim 1, wherein R2, R3 and R4 are each H.
i 7. The compound according to claim I, wherein Rn is a Ci-C,saikyi.
18. The compound according to claim 1, wherein R16 is H or Cj-Cealkyl.
19. The compound according to claim 1, wherein Q is selected from the group consisting of
CH2, S, -N-(Ci-C6alkyl), N-Y-(aryl) and -N-OMe.
20. The compound according to claim 1, wherein Q is S.
21. The compound according to claim 1, wherein Q is CH2.
22. The compound according to claim 1, wherein Q is -N-(CVC6alkyl).
23. The compound according to claim 1, wherein Q is -N-Y-(aryl).
24. The compound according to claim 1, wherein Q is -N-OMe.
25. The compound according to claim 1. wherein D is C-E.
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WO 2006/010264 PCT/CA2005/001177
26. The compound according to claim 1, wherein D is CH.
27. The compound according to claim 1, wherein L is C-R.
28. The compound according to claim 1, wherein R is H or halogen.
29. The compound according to claim 1, wherein L is N.
30. The compound according to claim 1, wherein E is selected from the group consisting of
E^ndE2.
31. The compound according to-claim 1, wherein E-is E -.
32. The compound according to claim 1, wherein E is E1, wherein E1 is selected from the
group consisting of H, halogen, ~C(O)NR42R43, -SO2NR42R43> C(=NR42)NR37R43, -CO2R42, -
C(O)(heterocyclyl), -C(O)(heteroaryl), -Y-(C6-Cio aryl}, -Y-(heteroaryI), -Y-(5 to 10 merabered
heterocyclic), -SR6\ -S(O)R6\ -SOaR08, wherein each of said E1 other than H and halogen are
optionally substituted with 1 to 5 independently selected R3S, or El is (Cl-C6)alkyl, which is
optionally substituted with 1 to 3 independently selected Y2 groups.
33. The compound according to claim 1, wherein R3? is selected from the group consisting
of halogen, -C(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -NR36R39, -OR37, d-Ceaikyl, -
CXCH2)jO(CH2)iNRJ6R39J -(CH2)nOR37, -SCOKC-Cgalkyl), -(CH2)n-(5 to 10 membered
heterocyclic), -(CH2)O(CH2)i(5 to 10 membered heterocyclic), -(CH2)n(5 to 10 membered
heteroaryl), -(CH2)jNR39(CH2)iNR36R39> -(CH2)jNR3p(CH2)nR36, -(CH2)nNR36R39, wherein j is
an integer ranging from 0 to 2, n is an integer ranging from 0 to 6, i is an integer ranging from 1
to 6,., the -(CH2)i- and -(CH2)«- moieties of the foregoing R38 groups optionally include a
carbon-carbon double or triple bond where n is an integer between 2 and 6, and the aikyl, aryl,
heteroaryl, and heterocyclic moieties of the foregoing R38 groups are optionally substituted by
one or more substituents independently selected from the group consisting of halo, cyano, nitro,
trifluoromethyl, azido, -OH, -C(O)R40, -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR36C(O)R39, -
C(O)NR36R39, -(CH2)nNR36R39, Ci-C6 alkyl, C3-CJ0 cycloalkyl -(CH2)n(C6-Ci0 aryl), -
(CH2)n(5-10 membered heterocyclyl), -(CH2)nO(CH2)iOR37, and -(CH2)nOR37, wherein n is an
integer ranging from 0 to 6 and i is an integer ranging from 2 to 6.
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34. The compound according to claim 1, wherein the alkyl, aryl, heteroaryl, and
heterocyclic moieties of the foregoing R groups are optionally substituted by one or more
substituents independently selected from the group consisting of-OH and -C(O)OR40.
35. The compound according to claim 1, wherein each R42 and R43 is independently
selected from the group consisting of H, -Y-(C3-Cio cycloalkyl), -Y-(C6-Cio aryl), -Y-(C6-Cio
heteroaryl) and -Y-(5 to 10 membered heterocyclic), wherein the cycloalkyl, aryl, heteroaryl
and heterocyclic moieties of the foregoing R42 and R43 groups are optionally substituted by 1 or
more substituents independently selected from R44.
36. The compound according to claim 1, wherein each R42 and R43 is independently
selected from the group consisting of H, CVC6 alkyl, Cj-Cs heteroalkyl, -Y'-CCVR37 and -Y-
OR37.
37. The compound according to claim 1, wherein one of R42 and R43 is H.
38. The compound according to claim 1, wherein one of R42 and R43 is -(Ce-Cio heteroary])
or -Y-(5 to 10 membered heterocyclic).
39. The compound according to claim 1, wherein Y is a bond.
40. The compound according to claim 1, wherein Y is -(C(R37)(H))fl.
41. The compound according to claim 1, wherein R42 and R4B taken together with the
nitrogen to which they are attached form a C5-C9 heterocyclyl ring or a heteroaryl ring, wherein
said ring is optionally substituted by 1 to 5 independently selected R44 substituents, with the
proviso that R42 and R43 are not both bonded to the nitrogen directly through an oxygen.
42. The compound according to claim 1, wherein R44 is independently selected from the
group consisting of-C(O)NR36R39, -OR37 and CrC6alkyl.
43. The compound according to claim 1, wherein each R40 is independently selected from
the group consisting of H and C1-C10 alkyl.
44. The compound according to claim 1, wherein each R36 and R39 is independently
selected from the group consisting of H, Ci-C6alkyl, -(CH2)n(5 to 10 membered heterocyclic), -
(CH2)nOR37 and -C(O)OR40, wherein n is an integer ranging from 0 to 6 and i is an integer
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WO 2006/010264 PCT/CA2005/00I177
ranging from 2 to 6, with the proviso that when R36 and R39 are both attached to the same nitrogen, then R36 and R39 are not both bonded to the nitrogen directly through an oxygen.
45. The compound according to claim 1, wherein each R37 and R4i is independently
selected from the group consisting of H and Ci-Qalkyl.
46. The compound according to claim 1, wherein Roa is selected from the group consisting
of -(CZ^Varyl, -(CZ5Z6)u-heteroaryl and CrC($alkyl, each of which is optionally substituted
with 1 to 3 indepedently selected Y3 groups, wherein u is 0,1, 2 or 3, and wherein when u is 2
or 3, the CZ5Z6 units may be the same or different
47. The compound according to claim 1, wherein R6a is selected from the group consisting
of -(CZ5Z6)u-aryl and -(CZ5Z6)u-heteroaryl, each of which is optionally substituted with 1 to 3
indepedently selected Y3 groups, wherein u is 0.
48. The compound according to clakn 1, wherein Y2 is -OH.
49. The compound according to claim 1, wherein Y3 is -OH.
50. The compound according to claim 1, wherein E" is -OC-(CR4SR45)n-R46' wherein n is
an integer ranging from 1 to 6.
51. The compound according to claim 50, wherein R45 is H.
52. The compound according to claim 50, wherein R4b is a heterocyclyl.
53. The compound according to claim 1, represented by the formula A-0:

and pharmaceutically acceptable salts and complexes thereof, wherein Z is O or S;
X and X1 are independently selected from the group consisting of H, Cj-Cg alkyl, halo, cyano and nitro, wherein Q-Cg aikyi is optionally substituted:
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WO 2006/010264 PCT/CA2005/001177
R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, halo,
trihalomethyl, -OR17, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein CrC6 alkyl,
C2-C6 alkenyl and C2-Ce alkynyl are optionally substituted; Q is O, S, NH, N(CrC6 alkyl), or N-Y-(aryl); DisCRu,orN; L is N, or CR, wherein R is H, halo, -CN, Ci-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein
C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 aikynyl are optionally substituted; and R7 is H, halogen, d-Q alkyl, -C(=O)NR9R10, -C(=O)(aryl), -C(=O)(heterocyclyI), -
C(^)(heteroaryl),-Y^aiyl),-Y-(heterocyclyl),-YH;heteroary}),-S-aryl,-»S-CrQ^llQrl,
-SO-Ci-Ce alkyl, -SO2-Ci-C6 alkyl, -Y-NR9R10, -SO2NR9R]0 or CO2R9, wherein Ci-C6
alkyl, aryl, heterocycle and heteroaryl are each independently optionally substituted; R9 and R10 are independently selected from H, CrC6 alkyl, -Y-(cycloalkyl), -Y-(aryl), -Y-
(heterocyclyl), -Y-(heteroaryl), -Y-O-Y^O-R11, -Y'-COs-R11, and -Y-O-R11, wherein
C1-C6 alkyl, cycloalkyl, aryl, heterocycle, and heteroaryi are each optionally substituted,
or R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted; Y is a bond or is -(C(Rn)(H))r, wherein t is an integer from 1 to 6; Y'is-(C(Rn)(H))r, R11 at each occurrence is independently H or C1-C6 alkyl, wherein Cy-Cc, alkyl is optionally
substituted, each R20 is independently selected from the group consisting of hydrogen, halo, trihalomethyl,
OR17, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein CrC6 alkyl, C2-C6 alkenyl
and C2-C6 alkynyl are optionally substituted, and each R17 is an independently selected CrQalkyl, wherein said Ci-C6alkyl is optionally
substituted.
54. The compound according to claim 53, wherein X and X1 are both hydrogen.
55. The compound according to claim 53, wherein R1 is hydrogen or halogen.
56. The compound according to claim 53, wherein R1 is fluorine.
57. The compound according to claim 53, wherein R4 is hydrogen or halogen.
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WO 2006/010264 PCT/CA2005/001177
58. The compound according to claim 53, wherein R4 is fluorine.
59. The compound according to claim 53, wherein R2 is selected from the group consisting
of H, halogen, trihalomethyl and -OR17.
60. The compound according to claim 53, wherein R3, and R20 are each hydrogen.
6L The compound according to claim 53, wherein R20 is -OR27.

62. The compound according to clam 53, wherein Q is S, N(Ci-C6 alkyl), or N-Y-(aryl).
63. The compound according to claim_53, wherein Q_is_NH.
64. The compound according to claim 53, wherein D is CR!'.
65. The compound according to claim 53, wherein L is CH or N.
66. The compound according to claim 53, wherein R7 is H. halogen,, Cj-Cg alkyl, -
CONR9R10, -SO2Mi2, -SG2NR9R!0, -Y-heterocydyl, -Y-heleroaryl, -S-aryl, -S-Ci-Ce alkyl, -
SG"C)-C6 alkyl, or -SCvQ-Q alky], wherein CrCs alkyl, is unsubstituted or is substituted
with, one or two of hydroxy or halogen, and heterocyclyl, and heteroaryi are unsubstituted or
substituted with one or two of alkoxy, alkyl, or haloalkyl.
67. The compound according to claim 53, wherein R7 is -CONR9R10.
68. The compound according to claim 53, wherein R7 is Y-heteroaryl.
69. The compound according to claim 67, wherein R9 and R10 are independently H, C1-C6
alky), -Y-O-R11, -Y-(heterocycle), -Yl-CO2-RH, or -Y-(aryl), wherein Ci-C6 alkyl is
unsubstituted or is substituted with one or two of hydroxy or halogen, and heterocyclyl, and
aryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, or haloalkyl.
70. The compound according to claim 67, wherein Rs and R10 are taken together with the
nitrogen to which they are attached to form a pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstituted or is substituted with
one or two of alkoxy, alkyl, or haloalkyl
71. The compound according to claim 53, wherein R7 is H, halogen, Ci-C$ alkyl, -
SO2NR9R10, -C(=O)(heterocyclyl), -Y-(heterocyclyl), or -Y-(heteroaryl), wherein Ci-Ce alkyl is
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WO 2006/010264 PCT/CA2005/001177
unsubstituted or is substituted with one or two of hydroxy or halogen, and heterocyclyl, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy, alkyi, or haloalkyl.
72. The compound according to claim 53, wherein Z is sulfur.
73. The compound according to claim 1, represented by the formula A-l:

and pharmaceutically acceptable salts and complexes thereof, wherein
R1 is selected from the group consisting of hydrogen, halo, Ci-Ce alkyi, C2-C6 alkenyl or C2-C6
alkynyl, wherein CrC6 alkyi. C2-C6 alkenyl and Cj-C^ alkynyl are optionally substituted;
X and X1 are independently selected from the group consisting of H and CpQ alkyi, wherein CrC6 alkyi is optionally substituted, or
X and X1 taken together with the atom to which they are attached, form a C3-C? cycloalkyl;
R7 is H, halogen, C,-C6 alkyi, -C(--=O)NR9R10, -C(=O)(aryl), -C(0)(heterocyclyl), -
C(=O)(heteroaryl), -Y-(aryl), -Y-(heterocyciyi), -Y-(heteroaryi), -SR6a, -S-axyl, -S-(heteroaryl), -S-CrC6 alkyi, -SO-CrC6 alkyi, -SOr-Ci-C* alkyi, -Y-NR9R10, -SO2NR9R!0, CO2R9, -CsC-(CR45R45)n-R46 and -C(=NR42)NR37R43, wherein n is an integer ranging from 0 to 6 and wherein C1-C6 alkyi, aryl, heterocycle and heteroaryl are each independently optionally substituted with 1 to 5 independently selected R38;
R9 and R10 are independently selected from H, CrC6 alkyi, -Y-(cycloalkyl), -Y-(CrC6
heteroalkyl), -Y-(aryl), -Y-(heterocyclyl), -Y-(heteroaryl), -Y-O-Y'-O-R11, -Y'-COi-Ru, Y-C(O)OR37 and -Y-O-R1', wherein, said Ci-C6 alkyl5heteroa!kyL cycloalkyl, aryl, heterocycle, and heteroaryi are each optionally substituted with one or more independently selected R44, or
R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9 heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted with 1 to 5 independently selected R44; each R20 is independently selected from the group consisting of H, halo, -OR17 and -C(O)OR17;
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WO 2006/010264 PCT/CA2005/0O1177
Y is a bond or is -(C(Rn)(H))r, wherein t is an integer from 1 to 6; Yl is -(C(Ru)(H))r, and
74. R1' at each occurrence is independently H or C\-Ca alkyl, wherein Cj-C6 alkyl is
optionally substituted.
75. The compound according to claim 73, wherein R1 is hydrogen or halogen.
76. The compound according to claim 73, wherein R1 is fluorine.
77. The compound according to claim 73, wherein R7 is selected from the group consisting
of H, -C(=O)NR9R10, -Y-(aryl), -Y-(heteroaryl) and -S-CrC6 alkyl, wherein said -Y-(aryl), -Y-
(heteroaryl) and -S-Ci-Ce alkyl axe optionally substituted with 1 to 5 independently selected
R3S.
78. The compound according to claim 73, wherein R7 is -C(=O)NR9R10, optionally
substituted with one or more independently selected R44.
79. The compound according to claim 73, wherein R' is -Y-(aryi), optionally substituted
with 1 to 5 independently selected R38.
80. The compound according to claim 73, wherein R7 is -Y-(heteroaryl)., optionally
substituted with 1 to 5 independently selected R3S.
81. The compound according to claim 73, wherein R3S is selected from the group consisting
of halogen. -OR37, CrC6alkyl, -(CH2)n-(5 to 10 membered heterocyclyl), -
(CH2)jNR39(CH2)nR36, -(CH2)jNR39(CH2)iNR36R39, -(CH^-heteroaryl, -C(O)NR36R39, -
(CK2)nO(CH2)i
integer ranging from 0 to 63 j is an integer ranging from 0 to 2, j is an integer ranging from 1 to
6 and wherein the alkyl, heteroaryl and heterocyclyl moieties of the foregoing R38 groups are
optionally substituted by one or more substituents independently selected from the group
consisting of halo, cyano, nitro, trifluoromefoyl, azido, -OH, -C(O)R40> -C(O)OR40, -OC(O)R40,
-OC(O)OR40, -NR36C(O)R39, -C(O)NR36R39, -(CH2)[lNR36R39) CrC6 alkyl, C3-C10 cycloalkyl, -
(CH2)n(C6-Cio aryl), -(CH2)n(5-10 membered heterocyclyl), -(CH2)nO(CH2)iOR37, and -
(CH^nOR3', wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6.
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82. The compound according to claim 73, wherein R38 is selected from the group consisting
of-OR37, Ci-C6alkyl, -(CH2)n(5 to 10 membered heterocyclyl) and -(CH2)nO(CH2)j(5 tolO
membered heterocyclyl).
83. The compound according to claim 73, wherein R9 and R10 are independently selected
from the group consisting of H, Ct-Cs alkyl, -Ci-Ce heteroalkyl, -Y-(aryl), -Y-(heterocyclyl), -
Y-(heteroaryl), -Y-O-R11 and Y-C(O)OR37, wherein a C.-C6 alkyl, CrC6 heteroalkyl, aryl,
heterocyclcyi and heteroaryl are each optionally substituted with 1 or more independently
selected R44.
84. The compound according to claim 73, wherein R44 is selected from the group consisting
of Cj-C6 alkyl, -OR37, -C(O)NR36R39 and ~C(0)OR46.
85. The compound according to claim 73, wherein R36 is selected from the grouip
consisting of H, CrC6 alkyl, -(CH2)nOR37 and -(CH2)n(heteroryclyl).
86. The compound according to claim 73, wherein R39 is H or Ci-Q alkyl.
87. The compound according to claim 73, wherein Ri> is H or Ci-Ce alkyl.
88. The compound according to claim 73, wherein R20 is selected from the group consisting
of K, halogen, -OR17 and -C(O)OR17.
89. The compound according to claim 73, wherein R17 is H or Ci-Cs alkyl.
90. The compound according to claim 73, wherein R20 is halogen.
91. The compound according to claim 73, wherein R20 is CJ or F.
92. The compound according to claim 73, wherein R6a is -(CZ5Z6)u-aryl.
93. The compound according to claim 73. wherein R7 is selected from the group consisting
of H, halogen, CrC6 alkyl, -CONR9^0, -SO2NH2, -SO2NR9R10, -Y-heterocyclyl, -Y-
heteroaryl, -S-aryl, -S-Ci-C6 a0
is unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocyclyl,
and heteroaryl are unsubstituted or are substituted with one or two of allcoxy, alkyl, or
haloalkyl.
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WO 2006/010264 PCT/CA2005/001177
94. The compound according to claim 73, wherein R7 is selected from the group
consisting of H, halogen, Ci-C6 alkyl, -SO2NReRi0, -C(=O)(heterocyclyl), -Y-(heterocyclyl), -
Y-(heteroaryl), -S-aryl. -S-CrC6 alkyl, -SO-CrC6 alkyl, or -SO2-Ci-C6 alkyl, wherein CrC6
alkyl is unsubstituted or is substituted with one or two of hydroxy or halogen, and the
heteroeyclyl, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy,
alkyl, or haloalkyl.
255
95. The compound according to claim 77, wherein R9 and R10 are independently selected
from the group consisting of H, C]~C6 alkyl. d-C6 heteroalkyl, -Y-O-R11, -Y-(heterocycIe), -Y-
CO2-RU, -Y-(aryl) and'Y-(heteroaryl),^vherein Ci-C
vvitli one or two of hydroxy or halogen, and the heterocyclyL aryl and heteroaryl are
unsubstituted or are substituted with one or two of alkoxy, alkyl, or haloalkyl.
96. The compound according to claim 77, wherein R9 and R10 are taken together with the
nitrogen to which they are attached to form a pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstituted or is substituted with
one or two of alkoxy, alky!, or haloallcyi.
97. The compound according to claim 77, wherein NR9R10 is selected from the group
consistisng of:

98. The compound according to claim 73, wherein R7 is unsubstituted heteroaryl.
99. The compound according to claim 73, wherein R7 is thiazolyl, pyridinyl, pyrimidinyl,
and imidazolyl, each of which is preferably unsubstituted or is substituted with one or two of
alkoxy, or alkyl.
100. The compound according to claim 73, wherein R7 is Ci-Ce alkyl, unsubstituted or
substituted with hydroxy.
101. The compound according to claim 73, wherein X and X! are both H.
102. The compound according to claim 73, wherein R17 is selected from the group consisting
of H and CrC6 alkyl.
103. The compound according to claim 73, wherein R38 is selected from the group consisting
of-OR37, Ci-C-6 alkyl and -(CH2)n(5 to 10 membered heterocylic), wherein n is an integer
ranging from 0 to 6.
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WO 2006/010264 PCT/CA2005/O01177
104. The compound according to claim 73, wherein R37 is selected from the group consisting
ofHandCi-Qalkyl.
105. The compound according to claim 1, represented by the formula A-2:

and pbarmaceutically acceptable salts and complexes thereof, wherein
R; is selected from the group consisting of hydrogen, halo, C|-C'6 alkyl, Cz-Ct, alkenyl or C2-Q alkyiryl, wherein Cj-C$ alkyl, C2-Cg alkenyl and Ca-C
K" is selected from the group consisting of H and halogen;
R7 is selected from the group consisting of H, halogen, Cj-Ce a)kyl. -C(=G)NR9R!0, -
C(=O)(ary1)= -C(=O)(heterocyclyl), -C(-O)(heteroaryl), -Y-(aiyl)s -Y~(heterocyclyl), -Y-Cheteroaryl), -S-atyl, -S-Cj-C6 alkyl, -SO-Cj-C* alkyl, -SOz-CrC6 alkyl, -Y-NR9Ri0, -SO;>NR9R!0 and CO2R95 wherein Ci-C6 alkyl, aryl, heterocycle and heteroaryl are each independently optionally substituted with 1 to 5 independently selected R38;
R9 and Ri0 are independently selected from the group consisting of H, C1-C6 alkyi, -Y-
(cyctoalkyl), -Y-(aryl), -Y-(heterocycly]), -Y-(heteroaryl), -Y-O-Y^O-R11, -Yl-CO2-Ru and -Y-O-Ru, wherein C1-C6 allcyl, cycloalkyl, aryl. heterocycle, and heteroarjd are each optionally substituted with one or more independently selected R44, or R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9 heterocycfyl ring or a heteroaryl ring, wherein said ring is optionally substituted;
Y is a bond or is -(C(Ru)(H))r, wherein t is an integer from 1 to 6;
Yjis-CCCR^CH^and
Ru at each occurrence is independently H or Ci-Ce alkyl, wherein Q-Q alkyl is optionally
substituted.
106. The compound according to claim 104, wherein R1 is hydrogen or halogen.
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WO 2006/010264 PCT/CA2005/001177
107. The compound according to claim 104, wherein R1 is fluorine.
108. The compound according to claim 104, wherein R4 is selected from the group consisting
of H and halogen.
109. The compound according to claim 104, wherein R4 is fluorine.
110. The compound according to claim 104, wherein R' is selected from the group consisting
of H, halogen, CrC6 alkyl, -C(=O)NR9R10, -SO2NH2, -SO2NR9R10, -Y-heterocyclyl -Y-
heteroaryl, -S-aryl, -S-Cj-C6 alkyl, -SO-Ci-C6 alkyl and ~SO2-C)-C6 alkyl, wherein CrC6 alkyl,
heterocyclyl, heteroaryl and aryl are^ach optionally-substituted with-1 to 5-independently
selected R38.
111. The compound according to claim 104, wherein R7 is selected from the group consisting
of H, halogen, C,-C6 alkyl, -C(=O)NR9R10, -SO2NH2, -SO2NR9R10, -Y-heterocyclyl -Y-
heteroaryl, -S-aryl, -S-CrC6 alkyl, -SO-CrC6 alkyl and -SO2-Ci-C6 alkyl, wherein Ci-C6 alkyl
is unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocyclyl,
and heteroaryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, haioalkyl or
(CH2)iNR39(CH2)nO(CH2)iOR37.
112. The compound according to claim 104, wherein R7 is selected from the group consisting
of H, halogen, CrC6 alkyl, -SO2NR9R10, -C(0)(heterocyclyl), -Y-(heterocyclyl), -Y-
(heteroaryl), -S-aryl, -S-Ci-C6 alkyl, -SO-CrC6 alkyl, or -SO2-Ci-C6 alkyi, wherein Ci-C6 alkyl
is unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocyclyl,
and heteroaryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, haioalkyl or
(CH2)jNR39(CH2)nO(CH2)iOR37.
113. The compound according to claim 104, wherein R7 is selected from the group consisting
of Ci-C6 alkyl, -C(=0)NR9Rio, -Y-(heterocyclyl, -Y-(heteroaryl)3 -S-CrC6 alkyl and -SO-Q-
C
halogen, and the heterocyclyl, and heteroaryl are unsubstituted or are substituted with one or
two of alkoxy, alkyl, haioalkyl or (C^jNRjgCCH^OCCH^iORsT.
114. The compound according to claim 104, wherein R7 is CONR9Ri0.
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115. The compound according to claim 113, wherein R9 and R10 are independently selected
from the group consisting of H, Cj-C6 alkyl, -Y-O-R11, -Y-(heterocyde), -Y'-CCVR11 and -Y-
(aryl), wherein the alkyl, heterocyclyl and aryl moieties of the foregoing R9 and R10 groups are
optionally substituted with 1 or more substituents independently selected from R44.
116. The compound according to claim 113, wherein R9 and R! ° are independently selected
from the group consisting of H, CrC6 alkyl, -Y-O-R1', -Y-(heterocycle), -Y1-CO2-RU and -Y-
(aryl), wherein Ci-C6 alkyl is unsubstituted or is substituted with one or two of hydroxy or
halogen, and the heterocyclyi, and aryl are unsubstituted or are substituted with one or two of
alkoxy, alkyl; haJoalkyl or (C^jNfogCCHolnOCCHaXORsv.
117. The compound according to claim 113, wherein Rs and R!0 taken together with the
nitrogen to which they are attached form a C5-C9 heterocyclyl ring or a heteroaryl ring, wherein
said ring is optionally substituted.
118. The compound according to claim 113, wherein R9 and R!0 are taken together with the
nitrogen to which they are attached to form a pyrrolidinyl, piperidirryl, piperazinyl,
morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstituted or is substituted with
one or two of alkoxy, alky!, or haloalkyl.
119. The compound according to claim 113, wherein NR9R10 is selected from the group
consisting of:

120. The compound according to claim 1, represented by the formula A-3 :
259

WO 2006/010264 PCT/CA2005/001177

and pharmaceutically acceptable salts and complexes thereof, wherein
R7 is selected from the group consisting of H, -Y-(aryl) and -Y-(heteroaryl), wherein -Y-(aryl)
and_-Y-(heteroaryl) are optionally substituted with 1 to 5 independently selected R38; R! is selected from the group consisting of hydrogen, halo, Ci-Q alkyl, C1-C6 alkenyl and C2-
Q alkynyl, wherein Q-Cb alkyl, C2-C
substituted; R12 is selected from the group consisting of H, Q-C6 allcyl, -O(Ci-C6 alkyl) and -Y-(aryl),
wherein Cj-Cg alkyl and aryl are optionally substituted; Y is a bond or is -(C(Rn)(H))r. wherein t is an integer from 1 to 6; R" is H or Ci-Ce aikyl, wherein Cj-C^ alkyi is optionally substituted: and each R2o is independently selected from the group consisting of H and halogen.
121. The compound according to claim 119, wherein R1 is hydrogen or halogen.
122. The compound according to claim 119, wherein R1 is fluorine.
123. The compound according to claim 119, wherein R12 is unsubsiituted C1-C3 alkyl or
unsubstituted -Y-phenyl.
124. The compound according to claim 119, wherein R20 is Cl.
125. The compound according to claim 1, represented by the formula A-4:

WO 2006/010264 PCT/CAZM5/001177
Z is O or S;
X and X1 are independently selected from the group consisting of H, Cj-C6 alkyl, halo, cyano
and aitro, wherein Cj-Q alkyl is optionally substituted; R1, R2, R3, R4, R3 and R6 are independently selected from the group consisting of hydrogen,
halo, CrC6 alkyl, Q2-C(> alkenyl, C2-C6 alkynyl andNR17R18, wherein CrC6 alkyl, C2~
C(, alkenyl and C2-C6 alkynyl are optionally substituted; R!7 and R18 are independently d-Cealkyl; Q is O, S, NH, N(CrC6 alkyl), or N-Y-(aryl); DisCR11, orNj L is N, or CR, wherein R is selected from the group consisting of H, halo, -CN, Cj-C
C2-C6- alkenyl and C2-C6 alkynyl, wherein CrC6 alkyi, C2-C6 alkenyl, and C2-C6 alkynyl
are optionally substituted; and
R13 is heterocyclyl or heteroaryl, wherein heterocyclyl and heteroaryl ai"e optionally substituted with 1 to 5 independently selected R3S;
Y is a bond or is -(C(Ru)(H))r, wherein t is an integer from 1 to 6; and R*" at each occurrence is independently H or Ci-Q aikyl, wherein C'I-C^ a'ikyi is optionally
substituted.
126. The compound according to claim 124, wherein X and X1 are both hydrogen.
127. The compound according to claim 124, wherein R1, R2, R3 and R4 are independently H
or halogen.
128. The compound according to claim 124, wherein R1 is hydrogen or halogen.
3 29. The compound according to claim 124, wherein R1 is fluorine or chlorine.

130. The compound according to claim 124, wherein R4 is hydrogen or halogen.
131. The compound according to claim 124, wherein R* is fluorine or chlorine.
132. The compound according to claim 124, wherein R2, R3, R5, and R6 are each hydrogen.
133. The compound according to claim 124, wherein Q is selected from the group consisting
of S, N(Ci-C6 alkyl) and N-Y-(aryl).
134. The compound according to claim 124, wherein Q is S.
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135. The compound according to claim 124, wherein D is CRU.
136. The compound according to claim 124, wherein R1! is H.
137. The compound according to claim 124, wherein L is CH or N.
138. The compound according to claim 124, wherein L is CH.
139. The compound according to claim 124, wherein Z is sulfur.
140. The compound according to claim 124, wherein R38 is selected from C(O)OR40 and
NR^R39,
141. The compound according to claim 124, wherein R40 is H or Ci-Cio alkyl.
142. The compound according to claim 124, wherein R36 and R39 are independently Cj-Ce
alkyl,
143. The compound according to claim 1, represented by the formula A-5:

and pharmaceutically acceptable salts and complexes thereof, wherein
R7 is selected from the group consisting of H, -C(O)NR42R4\ -Y-(aryl), -Y-(heteroaryl), -C(O)-
(C3-C10 cycloalkyl), -C(O)-(heterocyclyl), -C(O)-(C6-C10 aryl) and -C(O)-(heteroaryl),
wherein the aforementioned R7 groups other than H are optionally substituted with 1 to
5 independently selected R38;
R4 is selected from the group consisting of H and halogen; and T is selected from the group consisting of cycioalkyl, heterocyclyl, aryl, heteroaryl and
arylalkyl, each of which is optionally substituted with 1 to 3 independently selected R20;
144. The compound according to claim 142, wherein R' is selected from the group consisting
of H, C(O)NR42R43 and -Y-(heteroaryl), wherein -Y-(heteroaryl) is optionally substituted with
1 to 5 independently selected R38.
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WO 2006/010264 PCT/CA2005/001177
145. The compound according to claim 142, wherein R7 is C(O)NR42R43.
146. The compound according to claim 142, wherein R42 and R43 taken together with the
nitrogen to which they are attached form a C5-C9 heterocyclyi ring, wherein said ring is
optionally substituted with 1 to 5 independently selected R44 substituents, with the proviso that
R42 and R43 are not both bonded to the nitrogen directly through and oxygen.
147. The compound according to claim 142, wherein R4 is halogen.
148. The compound according to claim 142, wherein R4 is fluorine.
149. The compound according to claim 1, represented by the formula A-6:

WO 2006/010264 PCT/CA2005/001177
R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted with 1 to 5 independently selected R44;
each R20 is independently selected from the group consisting of H, halo, -OR17 and -C(O)OR17;
Y is a bond or is -(C(R! ')(H))t-5 wherein t is an integer from 1 to 6;
Y1 is -( C(Rn)(H))r; and
Rn at each occurrence is independently H or Ci-Q alkyl, wherein Q-C6 alkyl is optionally substituted.
150. The compound according to claim 148, wherein R7 is selected from the group consisting
of H, C(O)NR9R10 and -Y-(heteroaryl), wherein -Y-(heteroaryl) is optionally substituted with 1
to 5 independently selected R38.
151. The compound according to claim 148, wherein R7 is C(O)NR9R10.
152. The compound according to claim 148, wherein R9 and R10 taken together with the
nitrogen to which they are attached form a C5-C9 heterocyclyl ring, wherein said ring is
optionally substituted with 1 to 5 independently selected R44 substituents.
153. The compound according to claim 148, wherein R7 is -Y-(heteroaryl), wherein said -Y- .
(heteroaryl) is optionally substituted with 1 to 5 independently selected R38.
154. The compound according to claim 148, wherein R7 is -Y-(heteroaryl), wherein said -Y-
(heteroaryl) is optionally substituted with one Cj-Q alkyl.
155. The compound according to claim 148, wherein R! is halogen.
156. The compound according to claim 148, wherein R is fluorine.
157. The compound according to claim 148, wherein R17 is selected from the group
consisting of H and Ci-Ce allcyl.
158. The compound according to claim 148, wherein R3S is selected from the group
consisting of-OR37, Ci-Q alkyl and -(CH2)n(5 to 10 membered heterocylic), wherein n is an
integer ranging from 0 to 6.
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WO 2006/010264 PCT/CA2005/001177
159. Tlie compound according to claim 148, wherein R37 is selected from the group
consisting of H and Cj-Ce alkyl.
160. The compound according to claim 148, wherein each R20 is independently selected from
the group consisting of H, halogen and -O-(Ci-C6)alkyl.
161. The compound according to claim 148, wherein two R20 are H and the third R2G is
selected from the group consisting of H, halogen and -O-(Ci-C
162. A compound of the formula (B), that are inhibitors of VEGF receptor signaling and
HGF receptor signaling:
and pharrnaceutically acceptable salts and complexes thereof, wherein
T is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein
each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with 1 to 3
RM;
each R20 is independently selected from the group consisting of -H, halogen, trihalomethyl, -CN, -NO2, -NH2, -OR17, -OCF3j -NRi7R18? -S(O)0-2R17, -S(O)2NR17R17, -C(O)OR17, -C(O)NR17R17, -N(R17)SO2R17, -N(RI7)C(O)Rn, ~N(R!7)C(O)ORn5 -C(O)R17, -C(O)SRn, Ci-Q alkoxy, C;-C4 alkylthio, -O(CB2)natyl -O(CH2)nheteroaryI, -(CH2)o-5(aryi), -(CH2)o-5(heteroaryI)5 CrC6 alkyl, C2-Q alkenyl, C2-Q alkynyl, -CH2(CH2)0^-T25 an optionally substituted CM alkylcarbonyl, CM alkoxy, an amino optionally substituted by CM alkyl optionally substituted by CM aikoxy and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMe, -OEt, -NH2, -NHMe, -NMe2, -NHEt and -NEt2, and wherein the aryl, heteroaryl, Cj-Cg alkyl, C2-C6 aikenyl, and C2-C6 alkynyl are optionally substituted;
W is selected from the group consisting of 0, S and NH;
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WO 2006/010264 PCI7CA2005/0OI177
Z is selected from the group consisting of O, or S and NH;
X and X1 are independently selected from the group consisting of H, Ci-Cg alkyl, halo, cyano, or nitro, wherein Cj-C6 alkyl is optionally substituted, or
X and X1 taken together with the atom to which they are attached, form a C3-C7 cyeloalkyl;
R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, halo,
trihaiomethyi, -CN, -NO2, -NH2, -OR17, -NR17R18, -C(G)ORl\ -C(O)R", d~C4 alkoxy, C1-C4 alicylthio, CVC6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein Ci-C$ alkyl, C2-Ce alkenyl and C2-C6 alkynyl are optionally substituted;
R17 is-selectedXrom the group consisting of H and R18;
R1S is selected from the group consisting of a Q-Cealkyl, an aryl, a, aryl(Ci-C6alkyl), a
heterocyclyl and a heterocyclyl(Ci-C6alkyl), each of which is optionally substituted, or
R17 and R18, taken together with a common nitrogen to which they are attached, form an
optionally substituted five- to seven-membered heterocyclyl, the optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from the group consisting of N, O, S and P;
R's is selected from the group consisting of-H, -CN, -(CK2)o-5(aryl), -(CK2)o-5(heteroaryl), CV Ce alkyi, C2-C6 alkenyl, C2-C6 alkynyl, -CH2(CH2)o-4-T2, an optionally substituted C4-4 alkylcarbonyl, and a saturated or unsaturated three- to seven-membered carboxyclic or heterocyclic group, wherein T2 is selected from the group consisting of-OH, -OMe, -OEt, -NH2, -NHMe, -NMe2j -NHEt and -NEt2, and wherein the aryl, heteroaryl, Ci-C6 allcyl, C2-Q5 alkenyl, and C0-C6 alkynyl are optionally substituted;
D is selected from the group consisting of Oh, O, S, NH, N-(Ci-Ce alkyl), or N-Y-(aryl), -N-
OMe, -NCH2OMe and -N-Bn;
Q is selected from the group consisting of C-E and N;
L is N, or CR, wherein R is selected from the group consisting of -H, halo, -CN, Ci-Ce alkyl, C2-C0 alkenyl, and C2-C6 allcynyl, wherein Ci-Cg alkyi, C2-C6 alkenyl. and C2-C6 alkynyl are optionally substituted; and
E is selected from the group consisting of E , E and E , wherein
E1 is selected from the group consisting of -H, halogen, nitro, azido, Cj-Q allcyl, C3-C10 cyeloalkyl, -C(O)NR42R43, -Y-NR42R43, -NR42C(=O)R43, -SO2R42, -SO2NR42R43, -NR37SO2R42, -NR37SO2NR42R43, -C(=N-OR42)R43, -C(=NR42)R43.. -NR37C(=NR42)R43, -
266

WO 2006/010264 PCT/CA2005/0OII77
membered heterocyclyl), -(CH2)n0(CH2)j0R37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6;
each R42 and R43 is independently selected from the group consisting of H, C-i-Q alkyl, Ci-C6 heteroalkyi, -Y-(C3-C10 cycloalkyl), -Y-(C6-C!0 aryl), -Y-(C6-Cio heteroaryl), -Y-(5-10 membered heterocyclic), -Y-O-Y^OR37, -Y1-CO2-R37, and -Y-OR37, wherein the alkyl, heteroalkyi, cycloalkyl, aryl, heteroaryi and heterocyclic moieties of the foregoing R42 and R43 groups are optionally substituted by 1 or more substituents independently selected from R44, wherein
Y is a bond or is -(€{R37)(H))n, -
n is an integer ranging from 1 to 6, and
Y'is-CCCR^XH^or
R42 and R43 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted by 1 to 5 R44 substituents, with the proviso that R42 andR4j are not both bonded to the nitrogen directly through an oxygen;
each R44 is independently selected from the group consisting of halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, ~C(O)R4C', -C(O)OR40, -OC(O)R40, -OC(O)OR40, -NR3dC(O)R39, -C(O)NR36R39, -NR36R39, -OR37, -SO2NR36R39, -SO2R36, -NR36SO2R39, -NR36SO2NR37R4!, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C[0 cycloalkyl, -CrC6 alkylamino, -(CHz^OCCH^iNR3^39, ~(CH2)nO(CH2)iOR37, -(CPI2)nOR37, -S(O)j(CrC6 alkyl), -(CH2)n(C6-C]0 aryl), -(CH2)n(5-10 membered heterocyclic), -C(O)(CH2)n(C6-C10 aryl), -(CH2)nO(CH2)j(C6-C10 aryl), -(CH2)nO(CH2),(5 to 10 membered heterocyclic), -C(O)(CH2)n(5 to 10 membered heterocyclic), -(CH2)jNR39(CH2)iNR36R39, -(CH2)JNR39CH2C(O)NR36R39, -(CH2)jNR39(CH2)iNR37C(O)R4V(CH2)jNR39(CH2))10(CH2)iOR37,-(CH2)iNR39(CH2)iS(O)J(CrC6 alkyl), -(CH2)jNR39(CH2)nR36, -SO2(CH2)n(C6-C10 aryl), and -SO2(CH2)n(5 to 10 membered heterocyclic) wherein, j is an integer from 0 to 2, n is an integer from 0 to 6 and i is an integer ranging from 2 to 6, the -(CH2)i- and -(CH2)nr moieties of the foregoing R44 groups optionally include a carbon-carbon double or triple bond wherein n is an integer from 2 to 6. and the alkyl, aryl and heterocyclic moieties of the foregoing R"" groups are optionally substituted by 1 or more substituents
268

WO 2006/010264 PCT/CA2005/001177
independently selected from the group consisting of halo, cyano, nitro, trifiuoromethyl, azido, -OH, -C(O)R40, ~C(O)OR40, -OC(O)R40, -OC(O)OR40,-NR36C(O)R39, -C(O)NR36R39, -(CH2)nNR36R39, -SO2R36, -SO2NR36R39, CrC6 alkyl C3-C,o cycloalkyl, -(CH2)n(C6"Cio aryl), -(CH2)n(5 to 10 membered heterocyclic), -(CH2)nO(CH2)jOR37 and -(CH^nOR37, wherein n is an integer from 0 to 6 and i is an integer from 2 to 6: and
each R40 is independently selected from H, Ci-Cio aikyl, -(eH2)n(C6-Cio aryl), C3-C10
cycloalkyl, and -(CH2)O(5-10 membered heterocydic). wherein n is an integer ranging from 0 to 6;
eachR36 and R39 is independently selected from the. group consisting of H, -OH, Gi-Cg alkyl, "~ C3-C10 eyciualkyl, -(CHaMCs-Cio aryl), -(CH?.),j(5-iG membered heterocyclic), -(CH2)n0(CH2)i0R37? -(CH2)nCN{CH2)f;OR373 -(CH2);]CN(CH3)nR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6", and the alky!, aryi and heterocyelic moieties of the foregoing R?o ana R39 groups are optionally substituted by one or more substituents indepeiidently selected from -OH, halo, cyano, nitro, triiiuoiomelhy], azido, -C(O)R40, -0(0)0^, -CO(O)R40, -OC(O)OR48. -NR37C(O)R41, -C^NR37^", 'NR37R41, -CrC6 alkyj, -(CH^fA-Cio aryl}, -(CH2)n(5 to 10 membered heterocyclic), -(CH2)DO(CH2)jOR37, and -(CH2)nOR37, wherein n is an integer ranging from 0 to 6 and i is an integer ranging from 2 to 6, with the proviso that when Rj6 and R39 are both attached to the same nitrogen, then R36 and R39 are not both bonded to the nitrogen directly through an oxygen;
each R37 and R41 is independently selected from the group consisting of K, OR36, Ci-Ce alkyl
at'd C3-C10 cycloalkj'l;
each R6a and R6b is independently selected from the group consisting of hydrogen, -(CZ:!Z6)U-(C3-C6)cycloalkyla-(CZ5Z6)u-(C5-C6)cycloalkenyl,-(CZ5Zfl)u-aryl,-(CZ5Z6)u-heterocycle, (C2-C6)alkenyl, and (Cj-C6)alkyl, which is optionally substituted with 1 to 3 independently selected Y3 groups, where u is 0,1,2, or 3, and wherein when u is 2 or 3, the CZ5Z6 "units may be the same or different, or
R6a and R6b taken together with adjacent atoms can form a heterocycle;
each Z33 Z4, Z5 and Z6 is independently selected from the group consisting of H, F and (Ci-C6)alkyl, or
each Z3 and Z4, or Z5 and Z6 are selected together to form a carbocycle, or
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WO 2006/010264 PCT/CA2005/001111
two ZJ groups on adjacent carbon atoms are selected together to optionally form a carbocycle;
each Y2 and Y3 is independently selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, rnethylguanidino, azido, -C(O)Z7, -OC(O)NH2;, -OC(O) NHZ7, -OC(O)NZ7Z8, -NHC(O)Z7, -NHC(O)NH2, -NHC(O)NHZ7, -NHC(O)NZ7Z8, -C(O)OH, -C(O)OZ7, -C(O)NH2, -C(O)NHZ7,-C(O)NZ7Z8, -P(O)3H2? -P(O)3(Z7)2, -S(O)3H, -S(O)Z7, -S(O)2Z\ -S(O)3Z7, -Z7, -OZ75 -OH, -NH2, -NHZ7, -NZ7Z8, -C(=NH)NH2,-C(=NOH)NH2, -N-morpholino, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cr C6)haloalkyl, (C2-C6)haloalkenyl, (C2-C5)haloalkynyl, (CrC6)haLoalkoxy, -(CZ^^NH^-CCZ^NHZ^^^^
X6(CZ9Z10)r(C5-C8)cycloalkenyl, -X6(CZ9Z10)raryI and -X6(CZ9Z!0)rheterocycle, wherein
ris 1,2, 3 or 4;
X6 is selected from the group consisting of O, S, NH, -C(O)-; -C(O)NH-, -C(O)O-, -S(O>, -S(O)2-and-S(O)3-;
Z' and Z" are independently selected from the group consisting of an alky! of 1 to 12 carbon atoms, an alkenyl of 2 to 12 carbon atoms, an aikynyi of 2 to 12 carbon atoms, a cycloalkyl of 3 to 8 carbon atoms, a cycioaikenyl of 5 to 8 carbon atoms, an aryi of 6 to 14 carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7 to 15 carbon atoms, and a heteroaralfcyl of 5 to 14 ring atoms, or
Z7 and Z8 together may optionally form a heterocycle;
Z9 and Z10 are independently selected from the group consisting of H, F, a (Ci-Ci2)alkyl, a (C6-C}
Z9 and Z10 are taken together form a carbocycle, or
two Z9 groups on adjacent carbon atoms are taken together to form a carbocycle; or
any two Y2 or Y3 groups attached to adjacent carbon atoms may be taken together to be -O[C(Z9)(ZI0)]rO or -O[C(Z9)(Z10)]r+1, or
any two Y2 or Y3 groups attached to the same or adjacent carbon atoms may be selected together to form a carbocycle or heterocycle; and wherein
any of the above-mentioned substituents comprising a CH3 (methyl), CH2 (methylene), or CH (methine) group which is not attached to a halogen, SO or SO2 group or to a N, O or S
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WO 2006/01026-4 PCT7CA2005/001177
atom optionally bears on said group a substituent selected from hydroxy, halogen, (Q-C4)alkyl, (CrC4)alkoxy and an -N[(Ci-C4)alkyl3[(Cl-C4)alIcyl];
E2 is -OCH or -C=C-(CR45R45)n-R46;
R45 is independently selected from the gi"oup consisting of H, a (Ci-C6)alkyl and a (C3-Cs)cycloalkyl;
R46 is selected from the group consisting of heterocyclyl, -N(R47)-C(O)-N(R47)(R48)5 -N(R47)-C(S)-N(R47)(R48), -N(R47)-C(O)-OR4S; -N(R47)-C(O)-(CH2)n~R48, -N(R47)-SO2R47, -(CH2)nNR47R48, ~(CH2)ftOR48, -(CH2)nSR49, -(CH2)nS(O)R49, -(CH2)nS(O)2R49, -OC(O)R49, -OC(O)OR49, -C(O)NR47R48, heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C$)alkoxy, -NO2, (CrC6)alkyl, -CN, -SO2R50 and -(CH2)nNR50R51, and aryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-Ca)alkoxy, -NO2} (Ci-C6)alk>i -CN, -SO2R50 and -(CH2)nNR50R31;
R47 and R4S are independently selected from the group consisting of H, (Cj-C6)allcyl, (C3-
C8)cycloallcyl, heterocyclyl, -(CH2)nNR50R51, -(CH2)nORs0! -(CH2)nC(O)R49, -C(O)2R49.. -(CH2/V,SR49>-(CH2)nS(O)R49,-(CII2)nS(O)2R49, -(CH2)nK9, -(CH2)nCN, ar>'loptionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-Cfi^lkoxy, -NO2, (C-Cejalkyi, -CN, -(CH2)nOR49, -(CH2)nheterocyclyl, -(CH2)nheteroaryl, -SO2R50 and -(CH2)nNR50R51, and heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, -CF3, (Ci-C6)alkoxy; -NO2, (Ci-C6)alkyl, -CN, -(CH2)nOR4S, -(CH2)nheterocyclyl, -(CH2)nheteroaryl, -SO2R50 and -(CH2)nNR50R51, or
R4' and R48, together with the atom to which they are attached, form a 3-8 membered ring;
R49 is selected from the group consisting of (Ci-C6)all
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WO 2006/010264 PCT/CA2005/001177
-(CH2)nNR50R5i, and heteroaryl optionally substituted with one or more substituents
selected from the group consisting of halo, -CF3, (Ci-Q)alkoxy, -NO2, (C[-C6)alkyl, -
CN, -SO2R50 and -(CH2)QNR5OR51; R50 and R51 are independently selected from the group consisting of H, (C1-C6)alkyl, (C3-
C8)cycloalkyl and -C(O)R45, or
R3U and RJI, together with the atom to which they are attached, form a 3-8 membered ring; and E3 is the group defined by -(Zll)-(Z12)m~(Zn)rah wherein Z11 is heterocyclyl or heterocyclylene;
- Z12^is selected from theLgxoupconsisting_oiOC(O3, OC(S) and C(O); Z13 is selected from the group consisting of heterocyclyl, aralkyl, N(H)R52, (C]-C3)alkyl, -OR52,
halo, S(O)2R56, (CrC3)hydi-oxyalkyi and (CrC3)haloaUcyl; misO or 1; ml isOor 1; R52 is selected from the group consisting of H, -(CH2)qS(O)2R545 R55NR53R535 (Ci-C3)alkyl, -
(CH2)qOR53, -C(O)R54 and -C(O)OR53; q is 0,1,2, 3 or 4; R53is(C,-C3)alkyl;
R54 is (CrC3)alkyi or N(H)R53;
R55is(Ci-C6)allcyl;and
R5° is selected from the group consisting of NH2, (Ci-C3)alkyl and OR52.
163. The compound according to claim 161, represented by the formula B-0:

WO 2006/010264 PCT/CA2005/001177
R1, R2, R3, R4, R5 and Rb are independently selected from the group consisting of hydrogen,
halo, Ci-Co alkyl, C2-C6 alkenyl and C2-Q alkynyl, wherein Cj-Ce alkyl, C2-C6 alkenyi
and C^-Ce alkynyl are optionally substituted; Q is O, S, NH, N(CrC6 alkyl), or N-Y-(aryl); L is N, or CR, wherein R is halo, -CN, Cf-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein
Cj-Cs aik>'l, C2-C6 alkenyl, and Ci-C-6 alkynyl are optionally substituted; and R7 is selected from the group consisting of H, halogen, Cj-Q alkyl, -C(=O)NR9R10, -
C(=O)(aryl), -C(=O)(heterocyclyl), -C(=O)(heteroaryl), -Y-(aryl), -Y-(heterocyclyl), -
Y-(heteroaryl), -Y-NR9R10, -SO?NR9R10 and CO2R9, wherein A-C6 alkyl, aryl,
heterocyclyl and heteroaryl are each optionally substituted; R^ aad R10 are independently selected from the group consisting of H, Cj-Ce alkyl, -Y-
(cycloalkyl), -Y-(aryl), -Y-(heterocycIyl), -Y-(heteroaryl), -Y-O-Y^O-R11, -Y'-CO2-
R11, and -Y-O-R11, wherein Cj-Cg alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl
are each optionally substituted, or R9 and R10 are taken together with the nitrogen to which they are attached to form a C5-C9
heterocyclyl ring or a heteroaryi ring, wherein said ring is optionally substituted; R8 is selected from the group consisting of H, halo and Ci-Cg alkyl, wherein C1-C6 alkyl is
optionally substituted;
Y is a bond or is -(C(RI')(H))r, wherein t is an integer from 1 to 6; Y1is-(C(R")(H))r,and Ru at each occurrence is independently H or Ci-Q alkyi, wherein CrC-e alkyl is optionally
substituted.
164. The compound according to claim 162, wherein X and X1 are both hydrogen.
165. The compound according to claim 162, wherein R1 is hydrogen or halogen.
166. The compound according to claim 162, wherein R1 is fluorine.
167. The compound according to claim 162, wherein R4 is hydrogen or halogen.
168. The compound according 10 claim 162, wherein R4 is fluorine.
169. The compound according to claim 162, wherein R2, R3, R5S and R6 are each hydrogen.
273

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170. The compound according to claim 162, wherein Q is S, N(Cj -Q alkyl), or N-Y-(aryl).
171. The compound according to claim 162, wherein L is CH or N.
172. The compound according to claim 162, wherein R8 is selected from the group consisting
of H, halo and Cj-C6 alkyl, wherein CrC6 alkyl is optionally substituted with OH or NRI4R15}
where R14 and R15 are independently H or Cr-C* alkyl, or R14 and R15 are taken together with
the nitrogen to which they are attached to form a C5-C9 heterocyclyl ring or a heteroaryl ring,
wherein said ring is optionally substituted.
- - 173. -The compound-according to-claimJ625 wherein R7 is_ selected from thgLgroup consisting of a halogen, d-C6 alkyl, -CONR9R10, -SO2NH2, -SO2NR9R10, -Y-heterocycle -Y-heteroaryl, -S-aryl, -S-Ci-Ce alkyl, -SO-CrC6 alkyl and -SO2-CrC6 alkyl, wherein Cj-C6 alkyl is unsubstituted or is substituted with one or two of hydroxy or halogen, and the heterocycle, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy, alkyl, or haloalkyl.
174. The compound according to claim 162, wherein R7 is -CONR9R10.
175. The compound according to claim 173, wherein R and R1 are independently selected
from the group consisting of H, CrC6 alkyl, -Y-O-R11, ~Y-(heterocyeie), -Y1-CO2-RU and -Y-
(aryl), wherein Ci-Ce alkyl is unsubstituted or is substituted with one or two of hydroxy or
halogen, and the heterocycle, and aryl are unsubstituted or are substituted with one or two of
alkoxy, alkyl, or haloalkyl.
176. The compound according to claim 173, wherein R9 and R10 are taken together with the
nitrogen lo which they are attached to form a pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstituted or is substituted with
one or two of alkoxy, alkyl, or haloalkyl.
177. The compound according to claim 162, wherein R7 is selected from the group consisting
of H, halogen, C,-C6 alkyf, -SO2NR9R10, -C(-O)(heterocyclyl)3 -Y-(heterocyclyl), -Y-
(heteroaryl), -S-aryl, -S-Cj-C6 alkyl, -SO-Cj-C6 alkyl and -SO2-CrC6 alkyl, wherein Ci-C6
alkyl is unsubstituted or is substituted with one or two of hydroxy or halogen, and the
heterocyclyl, and heteroaryl are unsubstituted or are substituted with one or two of alkoxy,
alkyl, or haloalkyl.
274

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178. The compound according to claim 162, wherein Z is sulfur.
179. The compound according to claim 16], represented by the formula B-1:

and pharmaceutically acceptable salts and complexes thereof, wherein
R1 is selected from the group consisting of hydrogen, halo. Ci-Cg alkyl, C2-C
Q alkynyl, wherein Ci-C6 alkyl, C2-Q alkeny! and C2-Q alkynyl are optionally
substituted; R7 is selected from the group consisting of H, halogen, Ci-C6 alkyl, -C(-0)NR9Rio5 -
C(=O)(aryl), -C(=O)(heterocyclyl), -C(=0)(heteroaryl), -Y-(aryi), -Y-(heterocyciyl), -
Y-Cheteroaiyl), -Y-NR9Rl0! ~SO2NRSR1() a.id CO2R9, wherein C-rC6 alkyl, aryl5
heterocycle and heteroaryl are each independently optiop.a!jy_sub5tiruted; R9 and R10 are independently selected from the group consisting of H, Cj-Cg alkyl, -Y-
(oycloalkyl), -Y-(aiyl)s -Y-(iieterocyciyl), -Y-(heleroaiyl), -Y-O-Y'-O-R", -Y1-CO2~
Rl\ and -Y-O-R'1, wherein CrQ alkyl, cycloalkyl, aryl, heterocj'cle, and heteroaryl
are each optionally substituted, or R9 and R10 taken together with the nitrogen to which they are attached form a C5-C9
heterocyclyl ring or a heteroaryl ring, wherein said ring is optionally substituted; Y is a bond or is ~(C(Ru)(H))r, -wherein t is an integer from 1 to 6; Yiis-(C(R!I)(H))r; R!1 at each occurrence is independently H or Cj-Ce alkyl, wherein Ci-C^ alkyl is optionally
substituted; and R12 is selected from the group consisting of EL Ci-Ct alkyl and -Y-(aryl), wherein C1-C6 alkyl
and aryl are optionally substituted.
180. The compound according to claim 178, wherein R1 is hydrogen or halogen.
181. The compound according to claim 178, wherein R1 is fluorine.
275

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182. The compound according to claim 178, wherein R12 is unsubstituted C1-C3 alkyl or
unsubstituted benzyl.
183. The compound according to claim 178, wherein R7 is -C(O)NR9Ri0.
184. The compound according to claim 178, wherein R7 is selected from the group consisting
of

wherein the members of said group are optionally substituted by 1 to 3 independently selected R38.
276
185. The compound according to claim 178, wherein R7 is selected from the group consisting of

WO 2006/030264 PCT/CA2005/001177

wherein the members of said group are optionally substituted with 1 to 3 independently selected R38.
186. A pharmaceutical composition comprising the compound according to claim 1 and a
pharmaceutically acceptable carrier.
187. A pharmaceutical compositioin comprising the compound according to claim 161 and a
pharmaceutically acceptable carrier.
188. A method of inhibiting VEGF receptor signaling and HGF receptor signaling, the
method comprising contacting the receptor with a receptor inhibiting amount of a compound
according to claim 1.
189. A method of inhibiting VEGF receptor signaling and HGF receptor signaling, the
method comprising contacting the receptor with a receptor inhibiting amount of a compound
according to claim 161.
190. A method of inhibiting VEGF receptor signaling and HGF receptor signaling in a cell,
the method comprising contacting the cell with a receptor inhibiting amount of a compound
according to claim 1.
191. A method of inhibiting VEGF receptor signaling and HGF receptor signaling in a cell,
the method comprising contacting the cell with a receptor inhibiting amount of a composition
according to claim 185.
192. A method of inhibiting VEGF receptor signaling and HGF receptor signaling in a cell,
the method comprising contacting the cell with a receptor inhibiting amount of a compound
according to claim 161.
193. A method of inhibiting VEGF receptor signaling and HGF receptor signaling in a cell,
the method comprising contacting the cell with a receptor inhibiting amount of a composition
according to claim 186.
277

WO 2006/010264 PCT/CA2005/001177
194. A method of inhibiting VEGF receptor signaling and HGF receptor signaling in an
animal, the method comprising administering to the animal a receptor inhibiting amount of a
composition according to claim 185.
195. A method of inhibiting VEGF receptor signaling and HGF receptor signaling in an
animal, the method comprising administering to the animal a receptor inhibiting amount of a
composition according to claim 186.
196. The method of claim 193, wherein the animal is a human.
197. Themethodofclaim-194, wherein the animal is ahuman. _ ._
198. A method of inhibiting proliferative activity of a cell, the method comprising contacting
the cell with an effective proliferative inhibiting amount of a compound according to claim 1.
199. A method of inhibiting proliferative activity of a cell, the method comprising contacting
the cell with an effective proliferative inhibiting amount of a compound according to claim
161.
200. A method of treating a cell proliferative disease in a patient, the method comprising
administering to the patient in need of such treatment an effective therapeutical amount of a
composition according to claim 185.
201. A method of treating a cell proliferative disease in a patient, the method comprising
administering to the patient in need of such treatment an effective therapeutical amount of a
composition according to claim 186.
202. The method of claim 199, wherein the patient is a human.
203. The method of claim 201, wherein the cell proliferative disease is cancer.
204. The method of claim 200, wherein the patient is a human.
205. The method of claim 203, wherein the ceil proliferative disease is cancer.
206. A method of inhibiting tumor growth in a patient, the method comprising administering
to the patient in need thereoof an effective therapeutical amount of a composition according to
claim 185.
278

WO 2006/010264 PCT/CA2005/001177
207. A method of inhibiting tumor growth in a patient, the method comprising administering
to the patient in need thereof an effective therapeutical amount of a composition according to
claim 186.
208. The method of claim 205, wherein the patient is a human.
209. The method of claim 206, wherein the patient is a human.